Second Read, daily literature surveillance with an independent check
New evidence on how EGFR-mutant non-small cell lung cancer becomes resistant to osimertinib, how often each mechanism occurs, and what works after resistance.
19 papers need a reviewer. 9 accepted with every check passed. 9 excluded at screening.
Papers where a check failed come first. Each flag names the field and what went wrong, so the reviewer goes straight to it.
Lung Cancer, 2026. PMID 42918663. Found by the main search.
J Med Chem, 2026. PMID 42911709. Found by the main and second search.
In a cell-line study addressing acquired resistance to third-generation TKIs via the EGFR C797S mutation, HQY1480 was identified as an effective and well-tolerated lead PROTAC. This compound demonstrated efficacy in EGFR-mutant NSCLC models resistant to third-generation TKIs.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | acquired resistance to third-generation tyrosine kinase inhibitors (TKIs), particularly through the EGFR C797S mutation | acquired resistance to third-generation tyrosine kinase inhibitors (TKIs), particularly through the EGFR C797S mutation | Passed | Supported |
| variant | EGFR C797S mutation | EGFR C797S mutation | Passed | Supported |
| drug | HQY1480 | we developed HQY1480 | Passed | Supported |
| setting | acquired resistance to third-generation TKIs | acquired resistance to third-generation TKIs | Passed | Supported |
| study type | cell-line study | Systematic linker and E3 ligase ligand optimization enabled potent and selective degradation of multiple clinically relevant EGFR mutants with single-digit nanomolar DC50 values. | Passed | Not in the abstract |
| finding type | other | These findings establish HQY1480 as an effective and well-tolerated lead PROTAC for EGFR-mutant NSCLC with acquired resistance to third-generation TKIs. | Passed | Not in the abstract |
| key finding | HQY1480 is an effective and well-tolerated lead PROTAC for EGFR-mutant NSCLC with acquired resistance to third-generation TKIs. | These findings establish HQY1480 as an effective and well-tolerated lead PROTAC for EGFR-mutant NSCLC with acquired resistance to third-generation TKIs. | Passed | Supported |
Epidermal growth factor receptor (EGFR) mutant-driven non-small cell lung cancer (NSCLC) frequently develops acquired resistance to third-generation tyrosine kinase inhibitors (TKIs), particularly through the EGFR C797S mutation.
In xenograft models, HQY1480 outperformed BI-4020, overcame osimertinib resistance, and effectively inhibited tumor growth at low doses, while inducing robust EGFR degradation in patient-derived xenografts.
In xenograft models, HQY1480 outperformed BI-4020, overcame osimertinib resistance, and effectively inhibited tumor growth at low doses, while inducing robust EGFR degradation in patient-derived xenografts.
In xenograft models, HQY1480 outperformed BI-4020, overcame osimertinib resistance, and effectively inhibited tumor growth at low doses, while inducing robust EGFR degradation in patient-derived xenografts.
Cancers (Basel), 2026. PMID 42882792. Found by the main and second search.
This two-patient feasibility study evaluated the potential of cfChIP-ddPCR for the longitudinal assessment of EGFR and MET transcriptional activity in liquid biopsies. The study focused on overcoming resistance associated with MET amplification using osimertinib and the MET-TKI crizotinib.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | MET amplification | MET amplification represents the most common bypass resistance mechanism | Passed | Supported |
| variant | MET amplification | MET amplification | Passed | Supported |
| drug | osimertinib, and the MET-TKI, crizotinib | the EGFR-TKI, osimertinib, and the MET-TKI, crizotinib | Passed | Supported |
| setting | overcoming this resistance | overcoming this resistance | Passed | Supported |
| study type | two-patient feasibility study | two-patient feasibility study | Passed | Supported |
| n patients | 2 | two patients | Passed | Supported |
| finding type | other | This two-patient feasibility study illustrates the potential of cfChIP-ddPCR for the longitudinal assessment of EGFR and MET transcriptional activity in liquid biopsies. | Passed | Supported |
| key finding | This two-patient feasibility study illustrates the potential of cfChIP-ddPCR for the longitudinal assessment of EGFR and MET transcriptional activity in liquid biopsies. | This two-patient feasibility study illustrates the potential of cfChIP-ddPCR for the longitudinal assessment of EGFR and MET transcriptional activity in liquid biopsies. | Passed | Supported |
Methods: Cell-free chromatin immunoprecipitation (cfChIP) targeting H3 lysine 36 trimethylation (H3K36me3) was employed to investigate the transcriptional activity of the EGFR and MET genes in serial liquid biopsies obtained from two patients with EGFR-mutated NSCLC.
Combination therapy with the EGFR-TKI, osimertinib, and the MET-TKI, crizotinib, has demonstrated clinical efficacy in overcoming this resistance.
Background/Objectives:MET amplification represents the most common bypass resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutated non-small cell lung cancer (NSCLC).
Conclusions: This two-patient feasibility study illustrates the potential of cfChIP-ddPCR for the longitudinal assessment of EGFR and MET transcriptional activity in liquid biopsies.
Adv Sci (Weinh), 2026. PMID 42875888. Found by the main search.
In a cell-line study of TKI-resistant models, the GAS6-MERTK axis was identified as a resistance mechanism to osimertinib in the context of EGFR mutations in exons 19, 20, and 21. Co-treatment with Bis-EM and TKIs delayed tumor relapses in an Fc-dependent manner across patient-derived xenografts harboring clinically challenging EGFR exon 20 insertions and other mutations.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | GAS6-MERTK axis | GAS6-MERTK axis as an important driver of drug resistance | Passed | Supported |
| variant | EGFR mutations in exons 19, 20, and 21 | EGFR Mutations in Exons 19, 20, and 21 | Passed | Supported |
| context | resistance to osimertinib | resistance to osimertinib | Passed | Supported |
| drug | Bis-EM | bispecific antibody, Bis-EM | Passed | Supported |
| setting | TKI-resistant | TKI-resistant spheroids | Passed | Supported |
| study type | cell-line study | GAS6 overexpression enhanced cancer cell survival | Passed | Not in the abstract |
| finding type | resistance mechanism | these findings identify the GAS6-MERTK axis as an important driver of drug resistance | Passed | Supported |
| key finding | Co-treatment with Bis-EM and TKIs delayed tumor relapses in an Fc-dependent manner across patient-derived xenografts harboring clinically challenging EGFR exon 20 insertions and other mutations. | Co-treatment with Bis-EM and TKIs delayed tumor relapses in an Fc-dependent manner across patient-derived xenografts harboring clinically challenging EGFR exon 20 insertions and other mutations. | Passed | Supported |
Re-analysis of clinical data unveiled elevated expression of GAS6 and its receptor MERTK in lung cancer patients developing resistance to osimertinib.
Resistance of lung cancer to EGFR-targeting tyrosine kinase inhibitors (TKIs) like osimertinib frequently results from secondary mutations or activation of bypass signaling pathways.
Re-analysis of clinical data unveiled elevated expression of GAS6 and its receptor MERTK in lung cancer patients developing resistance to osimertinib.
Functionally, GAS6 overexpression enhanced cancer cell survival, whereas a new anti-GAS6 antibody delayed tumor relapses in xenograft models.
Transl Lung Cancer Res, 2026. PMID 42870959. Found by the main and second search.
In OS-resistant cells, the combination of pirfenidone with osimertinib or afatinib targets p38γ-mediated PI3K/AKT/mTOR signaling and p38γ-independent autophagy pathways. This combination demonstrated significant synergistic antitumor effects in NSCLC models, achieving Bliss synergy scores exceeding 14.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | p38γ-mediated PI3K/AKT/mTOR signaling pathway and p38γ-independent autophagy pathway | PFD enhances the efficacy of EGFR-TKIs through a dual mechanism: first, by specifically inhibiting the p38γ-mediated PI3K/AKT/mTOR signaling pathway, and second, by activating a p38γ-independent autophagy pathway. | Passed | Supported |
| context | OS-resistant cells | this combination successfully restored drug sensitivity in OS-resistant cells | Passed | Supported |
| drug | pirfenidone (PFD) in combination with osimertinib (OS) or afatinib (AF) | evaluate the synergistic antitumor effects of PFD in combination with OS or AF | Passed | Supported |
| setting | OS-resistant cells | restored drug sensitivity in OS-resistant cells | Passed | Supported |
| study type | cell-line study and in vivo validation | an HCC827 nude mouse xenograft model was employed for in vivo validation | Passed | Supported |
| finding type | resistance mechanism | Mechanistic investigations revealed that PFD enhanced EGFR-TKI sensitivity via two distinct pathways: firstly, by specifically inhibiting p38γ, a critical mediator of resistance, which leads to the downregulation of the PI3K/AKT/mTOR signaling pathway; and secondly, by promoting the autophagy cascade in a p38γ-independent manner. | Passed | Supported |
| key finding | The combination of PFD with either OS or AF exhibited significant synergistic antitumor effects in both in vitro and in vivo NSCLC models, consistently achieving Bliss synergy scores exceeding 14. | The combination of PFD with either OS or AF exhibited significant synergistic antitumor effects in both in vitro and in vivo NSCLC models, consistently achieving Bliss synergy scores exceeding 14. | Passed | Supported |
Methods: EGFR-mutant NSCLC cell lines (PC9 and HCC827) and their OS-resistant derivatives (HCC827 OR) were utilized to evaluate cell proliferation by Cell Counting Kit-8 (CCK-8) assays and colony formation experiments.
Methods: EGFR-mutant NSCLC cell lines (PC9 and HCC827) and their OS-resistant derivatives (HCC827 OR) were utilized to evaluate cell proliferation by Cell Counting Kit-8 (CCK-8) assays and colony formation experiments.
Notably, this combination successfully restored drug sensitivity in OS-resistant cells and reversed acquired resistance to EGFR-TKIs.
Methods: EGFR-mutant NSCLC cell lines (PC9 and HCC827) and their OS-resistant derivatives (HCC827 OR) were utilized to evaluate cell proliferation by Cell Counting Kit-8 (CCK-8) assays and colony formation experiments.
Transl Lung Cancer Res, 2026. PMID 42870856. Found by the main and second search.
In a single-center retrospective cohort study of 52 patients with EGFR-mutant disease, continued osimertinib combined with anlotinib was evaluated after first-line osimertinib therapy. This combination demonstrated encouraging antitumor activity in the setting of gradual progression.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | gradual progression | gradual progression | Passed | Supported |
| variant | EGFR-mutant | EGFR-mutant | Passed | Supported |
| context | after first-line osimertinib therapy | following first-line osimertinib therapy | Passed | Supported |
| drug | osimertinib combined with anlotinib | osimertinib in combination with anlotinib | Passed | Supported |
| setting | after first-line osimertinib therapy | following first-line osimertinib therapy | Passed | Supported |
| study type | single-center retrospective cohort study | single-center retrospective cohort study | Passed | Supported |
| n patients | 52 | 52 | Passed | Supported |
| finding type | treatment after resistance | continued osimertinib combined with anlotinib demonstrated encouraging antitumor activity | Passed | Supported |
| key finding | continued osimertinib combined with anlotinib demonstrated encouraging antitumor activity | continued osimertinib combined with anlotinib demonstrated encouraging antitumor activity | Passed | Supported |
Methods: This retrospective study enrolled patients with unresectable stage III or IV EGFR-mutant non-squamous NSCLC who received first-line osimertinib therapy at The First Affiliated Hospital of University of Science and Technology of China between January 2021 and December 2024.
Subsequently, patients received combination therapy with osimertinib (80 mg orally once daily) plus anlotinib (10 mg orally on days 1-14 of every 3-week cycle).
Eligible patients developed gradual progression after first-line osimertinib therapy.
Methods: This retrospective study enrolled patients with unresectable stage III or IV EGFR-mutant non-squamous NSCLC who received first-line osimertinib therapy at The First Affiliated Hospital of University of Science and Technology of China between January 2021 and December 2024.
Life Sci, 2026. PMID 42869130. Found by the main and second search.
In a preclinical study of acquired osimertinib resistance, AXL overexpression was identified as a key mechanism. Inhibiting the MEK-ERK pathway alongside osimertinib restored sensitivity in these AXL-driven resistant tumor cells.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | AXL overexpression | The overexpression of anexelekto (AXL) is known to be associated with acquired resistance to osimertinib. | Passed | Supported |
| drug | MEK inhibitor with osimertinib | The combination use of MEK inhibitor with osimertinib reversed the acquired osimertinib resistance in vitro and in vivo. | Passed | Supported |
| setting | acquired osimertinib resistance | The combination use of MEK inhibitor with osimertinib reversed the acquired osimertinib resistance in vitro and in vivo. | Passed | Supported |
| study type | preclinical study | Our findings provide preclinical mechanistic support for potential use to targeting MEK-ERK signaling in AXL-associated osimertinib resistance and forfurther validation in patient-derived and clinical models. | Passed | Supported |
| finding type | resistance mechanism | In this study, we identified that activation of MEK-ERK pathway played a key role in AXL-driven acquired osimertinib resistance in NSCLC. | Passed | Supported |
| key finding | Inhibition of the MEK-ERK activation restored osimertinib sensitivity in AXL-driven resistant tumor cells. | Inhibition of the MEK-ERK activation restored osimertinib sensitivity in AXL-driven resistant tumor cells. | Passed | Supported |
Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the standard first-line treatment for patients with EGFR-activating mutation of late-stage non-small cell lung cancer (NSCLC), but the emergence of acquired resistance limits its efficacy in real use.
Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the standard first-line treatment for patients with EGFR-activating mutation of late-stage non-small cell lung cancer (NSCLC), but the emergence of acquired resistance limits its efficacy in real use.
In this study, we identified that activation of MEK-ERK pathway played a key role in AXL-driven acquired osimertinib resistance in NSCLC.
In this study, we identified that activation of MEK-ERK pathway played a key role in AXL-driven acquired osimertinib resistance in NSCLC.
Cancer Lett, 2026. PMID 42849656. Found by the main search.
In EGFR-mutant NSCLC, PRODH promotes the persistence of osimertinib tolerance by increasing mitochondrial respiration in an enzyme activity-independent manner. This resistance mechanism was identified through a cell-line study focusing on drug-tolerant persistence.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | PRODH promotes the persistence of osimertinib tolerance in NSCLC by increasing mitochondrial respiration in an enzyme activity-independent manner | PRODH promotes the persistence of osimertinib tolerance in NSCLC by increasing mitochondrial respiration in an enzyme activity-independent manner | FailedQuote is not in the abstract word for word. | Supported |
| context | EGFR-mutant NSCLC | in NSCLC | FailedNot in the quote: EGFR.The quote does not say this: EGFR-mutant. | Supported |
| drug | osimertinib | osimertinib | Passed | Supported |
| setting | drug-tolerant persistence | drug-tolerant persister (DTP) cells | Passed | Supported |
| study type | cell-line study | Here we report that proline dehydrogenase 1 (PRODH) promotes the persistence of osimertinib tolerance in NSCLC | Passed | Not in the abstract |
| finding type | resistance mechanism | Here we report that proline dehydrogenase 1 (PRODH) promotes the persistence of osimertinib tolerance in NSCLC by increasing mitochondrial respiration in an enzyme activity-independent manner. | Passed | Supported |
| key finding | PRODH promotes the persistence of osimertinib tolerance in NSCLC by increasing mitochondrial respiration in an enzyme activity-independent manner. | PRODH promotes the persistence of osimertinib tolerance in NSCLC by increasing mitochondrial respiration in an enzyme activity-independent manner. | FailedQuote is not in the abstract word for word. | Supported |
The emergence of drug-tolerant persister (DTP) cells poses a major obstacle to durable responses to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC).
Here we report that proline dehydrogenase 1 (PRODH) promotes the persistence of osimertinib tolerance in NSCLC by increasing mitochondrial respiration in an enzyme activity-independent manner.
Here we report that proline dehydrogenase 1 (PRODH) promotes the persistence of osimertinib tolerance in NSCLC by increasing mitochondrial respiration in an enzyme activity-independent manner.
Here we report that proline dehydrogenase 1 (PRODH) promotes the persistence of osimertinib tolerance in NSCLC by increasing mitochondrial respiration in an enzyme activity-independent manner.
Front Oncol, 2026. PMID 42846034. Found by the main search.
In a case report of a patient with HER2 amplification alongside a persistent EGFR mutation, trastuzumab deruxtecan was administered as fifth-line therapy. The treatment achieved a systemic partial response sustained over seven cycles, accompanied by the regression of intracranial lesions.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | HER2 amplification | HER2 amplification is a recognised but underreported off-target resistance mechanism | Passed | Supported |
| variant | HER2 (ERBB2) amplification | acquired HER2 (ERBB2) amplification | Passed | Supported |
| context | alongside persistence of the original EGFR mutation | alongside persistence of the original EGFR mutation | Passed | Supported |
| drug | trastuzumab deruxtecan | the patient received trastuzumab deruxtecan | Passed | Supported |
| setting | fifth-line therapy | as fifth-line therapy | Passed | Supported |
| study type | case report | a case report | Passed | Supported |
| n patients | 1 | We report the case of a 50-year-old man | FailedNumber not in the abstract: 1. | Supported |
| finding type | resistance mechanism | This case underscores HER2 amplification as a clinically actionable resistance mechanism | Passed | Supported |
| key finding | the patient received trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, as fifth-line therapy, achieving a systemic partial response sustained over seven cycles, with concurrent regression of intracranial lesions | the patient received trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, as fifth-line therapy, achieving a systemic partial response sustained over seven cycles, with concurrent regression of intracranial lesions | Passed | Supported |
We report the case of a 50-year-old man with metastatic NSCLC harbouring an EGFR exon 19 deletion who experienced disease progression through multiple lines of therapy, including 3 years of first-line osimertinib, platinum-based chemotherapy, atezolizumab-bevacizumab-paclitaxel-carboplatin, and repeated radiotherapy for intracranial metastases.
We report the case of a 50-year-old man with metastatic NSCLC harbouring an EGFR exon 19 deletion who experienced disease progression through multiple lines of therapy, including 3 years of first-line osimertinib, platinum-based chemotherapy, atezolizumab-bevacizumab-paclitaxel-carboplatin, and repeated radiotherapy for intracranial metastases.
Comprehensive genomic profiling at progression identified acquired HER2 (ERBB2) amplification, confirmed by immunohistochemistry (IHC 3+) and fluorescence in situ hybridisation, alongside persistence of the original EGFR mutation.
We report the case of a 50-year-old man with metastatic NSCLC harbouring an EGFR exon 19 deletion who experienced disease progression through multiple lines of therapy, including 3 years of first-line osimertinib, platinum-based chemotherapy, atezolizumab-bevacizumab-paclitaxel-carboplatin, and repeated radiotherapy for intracranial metastases.
Lancet Respir Med, 2026. PMID 42833236. Found by the main and second search.
In a phase 2 trial of 61 patients with sensitising EGFR mutations who experienced disease progression on a third-generation EGFR TKI, the combination of amivantamab, lazertinib, and bevacizumab demonstrated durable anti-tumour activity. This regimen represents a promising chemotherapy-sparing alternative for managing acquired resistance to third-generation EGFR tyrosine-kinase inhibitors.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | acquired resistance to a third-generation EGFR tyrosine-kinase inhibitor | acquired resistance to a third-generation EGFR tyrosine-kinase inhibitor | Passed | Supported |
| variant | sensitising EGFR mutation (exon 19 deletion or exon 21 L858R, or both) | sensitising EGFR mutation (exon 19 deletion or exon 21 L858R, or both) | Passed | Supported |
| context | disease progression following treatment with a third-generation EGFR TKI (osimertinib or lazertinib) given in the first-line or second-line setting | disease progression following treatment with a third-generation EGFR TKI (osimertinib or lazertinib) given in the first-line or second-line setting | Passed | Supported |
| drug | combined amivantamab, lazertinib, and bevacizumab | combined amivantanab, lazertinib, and bevacizumab | Passed | Supported |
| setting | acquired resistance to a third-generation EGFR TKI | acquired resistance to a third-generation EGFR TKI | Passed | Supported |
| study type | prospective, international, multicentre, single-arm, phase 2 trial | prospective, international, multicentre, single-arm, phase 2 trial | Passed | Supported |
| n patients | 61 | 61 patients were enrolled | Passed | Supported |
| finding type | treatment after resistance | Combined amivantamab, lazertinib, and bevacizumab showed durable anti-tumour activity, representing a promising chemotherapy-sparing alternative after progression on third-generation EGFR TKIs. | Passed | Supported |
| key finding | Combined amivantamab, lazertinib, and bevacizumab showed durable anti-tumour activity, representing a promising chemotherapy-sparing alternative after progression on third-generation EGFR TKIs. | Combined amivantamab, lazertinib, and bevacizumab showed durable anti-tumour activity, representing a promising chemotherapy-sparing alternative after progression on third-generation EGFR TKIs. | Passed | Supported |
Adults (aged ≥18 years) with advanced stage, pathologically confirmed non-squamous NSCLC harbouring a sensitising EGFR mutation (exon 19 deletion or exon 21 L858R, or both) with disease progression following treatment with a third-generation EGFR TKI (osimertinib or lazertinib) given in the first-line or second-line setting were included.
Adults (aged ≥18 years) with advanced stage, pathologically confirmed non-squamous NSCLC harbouring a sensitising EGFR mutation (exon 19 deletion or exon 21 L858R, or both) with disease progression following treatment with a third-generation EGFR TKI (osimertinib or lazertinib) given in the first-line or second-line setting were included.
We assessed the activity and safety of combined amivantanab, lazertinib, and bevacizumab-a chemotherapy-sparing strategy-for patients with EGFR-mutant NSCLC and acquired resistance to a third-generation EGFR TKI.
Methods: ETOP 18-21 AMAZE-lung was a prospective, international, multicentre, single-arm, phase 2 trial.
Cell Signal, 2026. PMID 42810632. Found by the main search.
In EGFR-mutant non-small cell lung cancer, the FSTL1-AKT-LPL-LTB4-STAT3-ZEB1 cascade transcriptionally suppresses EGFR expression, inducing an EGFR-low tumor-cell state that reduces osimertinib sensitivity. This resistance mechanism, identified in 12 clinical specimens, highlights the role of the CAF-LPL-STAT3 axis in acquired resistance to osimertinib, a context where trichlorolide (T4) combined with osimertinib is relevant.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | CAF-LPL-STAT3 axis | Targeting the CAF-LPL-STAT3 axis | Passed | Supported |
| context | EGFR-mutant non-small cell lung cancer (NSCLC) | epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) | Passed | Supported |
| drug | tripchlorolide (T4) combined with osimertinib | tripchlorolide (T4) combined with osimertinib | Passed | Supported |
| setting | Acquired resistance to osimertinib | Acquired resistance to osimertinib | Passed | Supported |
| study type | clinical specimens and cellular mechanism research | ATP viability assays on mixed tumor tissues from 6 patients, then adopted a validation cohort of 12 clinical specimens | Passed | Supported |
| n patients | 12 | validation cohort of 12 clinical specimens | Passed | Supported |
| finding type | resistance mechanism | The FSTL1-AKT-LPL-LTB4-STAT3-ZEB1 cascade transcriptionally suppresses EGFR expression and induces an EGFR-low tumor-cell state associated with reduced osimertinib sensitivity | Passed | Supported |
| key finding | The FSTL1-AKT-LPL-LTB4-STAT3-ZEB1 cascade transcriptionally suppresses EGFR expression and induces an EGFR-low tumor-cell state associated with reduced osimertinib sensitivity | The FSTL1-AKT-LPL-LTB4-STAT3-ZEB1 cascade transcriptionally suppresses EGFR expression and induces an EGFR-low tumor-cell state associated with reduced osimertinib sensitivity | Passed | Supported |
Background: Acquired resistance to osimertinib in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) arises from both tumor cell-intrinsic pathways and tumor microenvironmental cues.
Background: Acquired resistance to osimertinib in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) arises from both tumor cell-intrinsic pathways and tumor microenvironmental cues.
Background: Acquired resistance to osimertinib in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) arises from both tumor cell-intrinsic pathways and tumor microenvironmental cues.
Methods: We first performed ATP viability assays on mixed tumor tissues from 6 patients, then adopted a validation cohort of 12 clinical specimens.
Lung Cancer, 2026. PMID 42804885. Found by the main search.
In a real-world exploratory analysis of 31 patients with NSCLC harboring the EGFR L858R + T790M compound mutation, the expected advantage of osimertinib monotherapy over erlotinib was absent. This finding indicates that the co-occurrence of these variants within the same tumor may negate the anticipated benefit of osimertinib.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | EGFR L858R + T790M compound mutation | the EGFR L858R + T790M compound mutation | Passed | Not in the abstract |
| variant | EGFR L858R + T790M | EGFR L858R + T790M compound mutation | Passed | Supported |
| context | where both variants co-occur within the same tumor | where both variants co-occur within the same tumor | Passed | Supported |
| drug | erlotinib (Erlo) or osimertinib (Osi) monotherapy | receiving erlotinib (Erlo) or osimertinib (Osi) monotherapy | Passed | Supported |
| setting | real-world | Real-world progression-free survival (rwPFS) per treatment line | Passed | Supported |
| study type | exploratory analysis | An exploratory analysis | Passed | Supported |
| n patients | 31 | Thirty-one patients | Passed | Supported |
| finding type | other | suggest that the EGFR L858R + T790M compound mutation may represent a pharmacologically distinct entity with differential TKI sensitivity. | Passed | Not in the abstract |
| key finding | The expected osimertinib advantage was absent in L858R + T790M compound-mutant NSCLC. | The expected osimertinib advantage was absent in L858R + T790M compound-mutant NSCLC. | Passed | Supported |
Methods: Using the MSK-CHORD clinicogenomic dataset (n = 24,950), we identified patients with concurrent EGFR L858R and T790M mutations receiving erlotinib (Erlo) or osimertinib (Osi) monotherapy.
Methods: Using the MSK-CHORD clinicogenomic dataset (n = 24,950), we identified patients with concurrent EGFR L858R and T790M mutations receiving erlotinib (Erlo) or osimertinib (Osi) monotherapy.
Methods: Using the MSK-CHORD clinicogenomic dataset (n = 24,950), we identified patients with concurrent EGFR L858R and T790M mutations receiving erlotinib (Erlo) or osimertinib (Osi) monotherapy.
Genes (Basel), 2026. PMID 42792909. Found by the main search.
In a cell-line study of EGFR-mutant lung adenocarcinoma, the combination of osimertinib and capivasertib synergistically reduced cell viability in PC9 and H1975 cells after resistance development. The combination index values were 0.61 and 0.14, respectively, at Fa = 0.5.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | EGFR tyrosine kinase inhibitor resistance pathway | EGFR tyrosine kinase inhibitor resistance pathway | Passed | Supported |
| context | LUAD harboring EGFR mutations | lung adenocarcinoma (LUAD) harboring EGFR mutations | Passed | Supported |
| drug | osimertinib and capivasertib | osimertinib and capivasertib | Passed | Supported |
| study type | cell-line study | ectopic expression of miR-126-3p into LUAD cells | Passed | Supported |
| finding type | treatment after resistance | Combination therapy synergistically reduced cell viability in both PC9 and H1975 cells | Passed | Contradicted |
| key finding | Combination therapy synergistically reduced cell viability in both PC9 and H1975 cells, with combination index values of 0.61 and 0.14, respectively, at Fa = 0.5. | Combination therapy synergistically reduced cell viability in both PC9 and H1975 cells, with combination index values of 0.61 and 0.14, respectively, at Fa = 0.5. | Passed | Supported |
Methods: The antitumor function of miR-126-3p was analyzed by the ectopic expression of miR-126-3p into LUAD cells with EGFR mutation.
Therefore, we investigated the effect of combination therapy comprising osimertinib and capivasertib on LUAD cell viability.
Methods: The antitumor function of miR-126-3p was analyzed by the ectopic expression of miR-126-3p into LUAD cells with EGFR mutation.
Transl Lung Cancer Res, 2026. PMID 42870834. Found by the second search.
In a retrospective cohort of 29 heavily pretreated NSCLC patients with EGFR mutations who progressed on prior third-generation EGFR-TKI therapy, rechallenge with a third-generation EGFR-TKI was evaluated. This strategy achieved a median progression-free survival of 6.0 months and a median overall survival of 12.0 months.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| variant | EGFR mutation | EGFR-mutant non-small cell lung cancer | FailedThe quote does not say this: mutation. | Supported |
| context | after progression on prior third-generation EGFR-TKI therapy | after progression on prior third-generation EGFR-TKI therapy | Passed | Supported |
| drug | third-generation EGFR-TKI rechallenge | third-generation EGFR-TKI rechallenge | Passed | Supported |
| setting | heavily pretreated resistant NSCLC patients | heavily pretreated resistant NSCLC patients | Passed | Supported |
| study type | retrospective cohort study | retrospective cohort study | Passed | Supported |
| n patients | 29 | 29 patients | Passed | Supported |
| finding type | treatment after resistance | Third-generation EGFR-TKI rechallenge achieved a median progression-free survival (mPFS) of 6.0 months, a median overall survival (mOS) of 12.0 months. | Passed | Supported |
| key finding | Third-generation EGFR-TKI rechallenge achieved a median progression-free survival (mPFS) of 6.0 months, a median overall survival (mOS) of 12.0 months. | Third-generation EGFR-TKI rechallenge achieved a median progression-free survival (mPFS) of 6.0 months, a median overall survival (mOS) of 12.0 months. | Passed | Supported |
Methods: We retrospectively analyzed 29 patients with advanced EGFR-mutant NSCLC who received third-generation EGFR-TKI rechallenge after progression on prior third-generation EGFR-TKI therapy between December 2019 and August 2025.
Methods: We retrospectively analyzed 29 patients with advanced EGFR-mutant NSCLC who received third-generation EGFR-TKI rechallenge after progression on prior third-generation EGFR-TKI therapy between December 2019 and August 2025.
This study evaluated the efficacy and safety of third-generation EGFR-TKI rechallenge as a potential salvage option for heavily pretreated resistant NSCLC patients.
Methods: We retrospectively analyzed 29 patients with advanced EGFR-mutant NSCLC who received third-generation EGFR-TKI rechallenge after progression on prior third-generation EGFR-TKI therapy between December 2019 and August 2025.
Lancet Respir Med, 2026. PMID 42833237. Found by the second search.
Front Oncol, 2026. PMID 42818644. Found by the second search.
A case report describes a patient with concurrent EGFR exon 19 deletion, ERBB2 amplification, and ERBB2 p.S310F mutation who achieved a partial response in pulmonary lesions and a complete response in intracranial metastases after four cycles of trastuzumab rezetecan monotherapy. This treatment was administered after multiple lines of therapy.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | primary ERBB2 genetic alterations | primary ERBB2 genetic alterations | Passed | Supported |
| variant | EGFR exon 19 deletion, ERBB2 amplification, and ERBB2 p.S310F mutation | EGFR exon 19 deletion, ERBB2 amplification, and ERBB2 p.S310F mutation | Passed | Supported |
| context | concurrent | concurrent | Passed | Supported |
| drug | trastuzumab rezetecan | trastuzumab rezetecan | Passed | Supported |
| setting | after multiple lines of therapy | after multiple lines of therapy | Passed | Supported |
| study type | case report | Case Report | Passed | Supported |
| n patients | 1 | a case | FailedNumber not in the abstract: 1. | Supported |
| finding type | treatment after resistance | trastuzumab rezetecan may be a promising treatment option for EGFR-mutant NSCLC with concurrent ERBB2 genetic alterations, even after failure of multiple lines of treatment. | Passed | Supported |
| key finding | The patient achieved a partial response in pulmonary lesions and a complete response in intracranial metastases after four cycles of trastuzumab rezetecan monotherapy. | the patient achieved a partial response in pulmonary lesions and a complete response in intracranial metastases | Passed | Supported |
We report a case of advanced lung adenocarcinoma harboring concurrent EGFR exon 19 deletion, ERBB2 amplification, and ERBB2 p.S310F mutation.
The patient experienced disease progression after multiple lines of therapy, including osimertinib-based treatment, pemetrexed/carboplatin plus ivonescimab, and nab-paclitaxel plus Endostar.
The patient experienced disease progression after multiple lines of therapy, including osimertinib-based treatment, pemetrexed/carboplatin plus ivonescimab, and nab-paclitaxel plus Endostar.
We report a case of advanced lung adenocarcinoma harboring concurrent EGFR exon 19 deletion, ERBB2 amplification, and ERBB2 p.S310F mutation.
Cancer Med, 2026. PMID 42817873. Found by the second search.
In a real-world longitudinal study of 48 patients with metastatic NSCLC and breast cancer, ddPCR-based ctDNA monitoring enabled the early detection of acquired resistance mechanisms, including EGFR T790M and C797S, PIK3CA, BRAF, ERBB2/EGFR amplifications, and ESR1 mutations. This approach predicted disease progression significantly earlier than standard imaging in patients who had progressed on 1st/2nd-generation or 3rd-generation TKIs.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | acquired resistance (AR) | detecting acquired resistance (AR) | Passed | Supported |
| variant | EGFR T790M, EGFR C797S, PIK3CA, BRAF mutations, ERBB2/EGFR amplifications, ESR1 mutations (D538G, L536R, Y537S) | EGFR C797S was the main AR mechanism (47%), followed by PIK3CA, BRAF mutations, and ERBB2/EGFR amplifications | FailedNot in the quote: ESR1, D538G, L536R, Y537S. | Supported |
| context | progressed on 1st/2nd-generation TKIs; on 3rd-generation TKIs | patients who progressed on 1st/2nd-generation TKIs | FailedNot in the quote: 3rd. | Supported |
| drug | 1st/2nd-generation TKIs, 3rd-generation TKIs | 1st/2nd-generation TKIs | FailedNot in the quote: 3rd. | Supported |
| setting | metastatic non-small cell lung cancer (NSCLC) and breast cancer (MBC) | metastatic non-small cell lung cancer (NSCLC) and breast cancer (MBC) | Passed | Supported |
| study type | real-world, longitudinal study | real-world, longitudinal study | Passed | Supported |
| n patients | 48 | 48 metastatic patients | Passed | Supported |
| finding type | resistance mechanism | EGFR C797S was the main AR mechanism (47%), followed by PIK3CA, BRAF mutations, and ERBB2/EGFR amplifications | Passed | Supported |
| key finding | ddPCR-based ctDNA monitoring enables early detection of resistance and predicts disease progression significantly earlier than standard imaging in both NSCLC and MBC. | ddPCR-based ctDNA monitoring enables early detection of resistance and predicts disease progression significantly earlier than standard imaging in both NSCLC and MBC | Passed | Supported |
This real-world, longitudinal study included 48 metastatic patients (42 with EGFR-mutant NSCLC; 6 with HR+/HER2-negative MBC) treated at a Brazilian oncology reference center.
For patients on 3rd-generation TKIs, EGFR C797S was the main AR mechanism (47%), followed by PIK3CA, BRAF mutations, and ERBB2/EGFR amplifications.
For patients on 3rd-generation TKIs, EGFR C797S was the main AR mechanism (47%), followed by PIK3CA, BRAF mutations, and ERBB2/EGFR amplifications.
This real-world, longitudinal study included 48 metastatic patients (42 with EGFR-mutant NSCLC; 6 with HR+/HER2-negative MBC) treated at a Brazilian oncology reference center.
Clin Lung Cancer, 2026. PMID 42913244. Found by the main search.
In a phase II platform study of 31 patients with EGFR-mutated disease who progressed on first-line osimertinib, the combination of osimertinib and platinum-based chemotherapy was evaluated. This regimen demonstrated a modest clinical benefit and a manageable safety profile in this post-progression setting.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| variant | EGFR-mutated | EGFR-mutated | Passed | Supported |
| context | following progression on first-line osimertinib | following progression on first-line osimertinib | Passed | Supported |
| drug | osimertinib plus platinum-based chemotherapy | osimertinib plus platinum-based chemotherapy | Passed | Supported |
| setting | post-progression on first-line osimertinib | Post-progression on First-Line Osimertinib | Passed | Supported |
| study type | phase II, platform study | phase II, platform study | Passed | Supported |
| n patients | 31 | Thirty-one | Passed | Supported |
| finding type | treatment after resistance | osimertinib plus platinum-based chemotherapy demonstrated a modest clinical benefit and manageable safety profile | Passed | Supported |
| key finding | osimertinib plus platinum-based chemotherapy demonstrated a modest clinical benefit and manageable safety profile | osimertinib plus platinum-based chemotherapy demonstrated a modest clinical benefit and manageable safety profile | Passed | Supported |
Background: ORCHARD (NCT03944772) was a biomarker-directed, phase II, platform study conducted to characterize resistance mechanisms and evaluate novel treatment combinations in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) following progression on first-line osimertinib.
Methods: Patients received osimertinib (80 mg once daily) plus ≤ 4 cycles of platinum-based doublet chemotherapy (pemetrexed 500 mg/m2 plus carboplatin AUC5) on day 1 of every 21-day cycle, followed by pemetrexed maintenance until disease progression, unacceptable toxicity, or another discontinuation criterion.
Background: ORCHARD (NCT03944772) was a biomarker-directed, phase II, platform study conducted to characterize resistance mechanisms and evaluate novel treatment combinations in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) following progression on first-line osimertinib.
Background: ORCHARD (NCT03944772) was a biomarker-directed, phase II, platform study conducted to characterize resistance mechanisms and evaluate novel treatment combinations in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) following progression on first-line osimertinib.
Transl Lung Cancer Res, 2026. PMID 42870814. Found by the second search.
A post hoc analysis of 190 patients with EGFR-mutant disease who progressed on osimertinib evaluated amivantamab-chemotherapy as a treatment option. The study found that amivantamab-chemotherapy demonstrated superior progression-free survival compared to chemotherapy in Asian patients.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| variant | EGFR-mutant | EGFR-mutant | Passed | Supported |
| context | after progression on osimertinib | after progression on osimertinib | Passed | Supported |
| drug | amivantamab-chemotherapy | amivantamab-chemotherapy | Passed | Supported |
| setting | after progression on osimertinib | whose disease had progressed on osimertinib monotherapy | Passed | Supported |
| study type | post hoc analysis | post hoc analysis | Passed | Supported |
| n patients | 190 | 190 | Passed | Supported |
| finding type | treatment after resistance | Amivantamab-chemotherapy provides an effective option for patients whose disease had progressed on third-generation EGFR tyrosine kinase inhibitors. | Passed | Supported |
| key finding | Amivantamab-chemotherapy demonstrated superior PFS vs. chemotherapy in Asian patients. | Amivantamab-chemotherapy demonstrated superior PFS vs. chemotherapy in Asian patients. | Passed | Supported |
Background: The Phase 3 MARIPOSA-2 study showed that amivantamab, a bispecific antibody with immune cell-directing activity, plus chemotherapy significantly improved progression-free survival (PFS) compared with chemotherapy alone in participants with common epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), whose disease had progressed on osimertinib monotherapy.
Background: The Phase 3 MARIPOSA-2 study showed that amivantamab, a bispecific antibody with immune cell-directing activity, plus chemotherapy significantly improved progression-free survival (PFS) compared with chemotherapy alone in participants with common epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), whose disease had progressed on osimertinib monotherapy.
Amivantamab-chemotherapy provides an effective option for patients whose disease had progressed on third-generation EGFR tyrosine kinase inhibitors.
We conducted a post hoc analysis to assess clinical outcomes in the Asian subgroup of participants from MARIPOSA-2 (NCT04988295).
Every quote was found in the abstract, every number matched, and the second model supported every claim.
J Exp Clin Cancer Res, 2026. PMID 42919317. Found by the main and second search.
In preclinical models of EGFR-mutated lung adenocarcinoma with acquired resistance to osimertinib, the ERK/GATAD2A/SAA1 epigenetic-immune axis was identified as a key resistance mechanism. SAA1 serves as a bridge between tumor-intrinsic survival adaptations and microenvironmental immune suppression, suggesting that its neutralization could enhance the efficacy of EGFR-TKIs.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | ERK/GATAD2A/SAA1 epigenetic-immune axis | ERK/GATAD2A/SAA1 epigenetic-immune axis | Passed | Supported |
| context | EGFR-mutated lung adenocarcinoma | EGFR-mutated lung adenocarcinoma | Passed | Supported |
| drug | osimertinib | osimertinib | Passed | Supported |
| setting | acquired resistance | Acquired resistance | Passed | Supported |
| study type | preclinical models | patient-derived organoids, xenografts, and immunocompetent spontaneous lung tumor models | Passed | Supported |
| finding type | resistance mechanism | Our findings define a novel therapy-induced ERK/GATAD2A/SAA1 epigenetic-immune axis that drives acquired resistance to osimertinib. | Passed | Supported |
| key finding | SAA1 acts as a pivotal bridge between tumor-intrinsic survival adaptations and microenvironmental immune suppression, highlighting SAA1 neutralization as a tractable combinatorial strategy to enhance EGFR-TKI efficacy in LUAD. | SAA1 acts as a pivotal bridge between tumor-intrinsic survival adaptations and microenvironmental immune suppression, highlighting SAA1 neutralization as a tractable combinatorial strategy to enhance EGFR-TKI efficacy in LUAD. | Passed | Supported |
Background: Acquired resistance significantly limits the long-term clinical benefit of osimertinib in EGFR-mutant lung adenocarcinoma (LUAD).
Background: Acquired resistance significantly limits the long-term clinical benefit of osimertinib in EGFR-mutant lung adenocarcinoma (LUAD).
Conclusions: Our findings define a novel therapy-induced ERK/GATAD2A/SAA1 epigenetic-immune axis that drives acquired resistance to osimertinib.
Methods: We integrated transcriptomic profiling and clinical cohort analyses to identify therapy-induced secreted factors during the evolution of EGFR-TKI resistance.
Crit Rev Oncol Hematol, 2026. PMID 42906730. Found by the main search.
This narrative review examines the use of antibody-drug conjugates (ADCs) in the context of resistance to EGFR tyrosine kinase inhibitors, addressing mechanisms such as altered antigen expression, CNS involvement, and histological transformation. It proposes an eight-domain assessment of the post-progression disease state to distinguish ADC eligibility from therapeutic priority.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | actionable resistance mechanisms, altered antigen expression, central nervous system (CNS) involvement, spatial heterogeneity, and histological transformation | actionable resistance mechanisms, altered antigen expression, central nervous system (CNS) involvement, spatial heterogeneity, and histological transformation | Passed | Supported |
| context | after the development of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) | after the development of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) | Passed | Supported |
| drug | Antibody-drug conjugates (ADCs) | Antibody-drug conjugates (ADCs) | Passed | Supported |
| setting | after the development of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) | after the development of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) | Passed | Supported |
| study type | narrative review | This narrative review | Passed | Supported |
| finding type | other | This narrative review links agent-specific evidence boundaries to an eight-domain assessment of the post-progression disease state and distinguishes ADC eligibility from therapeutic priority. | Passed | Not in the abstract |
| key finding | This narrative review links agent-specific evidence boundaries to an eight-domain assessment of the post-progression disease state and distinguishes ADC eligibility from therapeutic priority. | This narrative review links agent-specific evidence boundaries to an eight-domain assessment of the post-progression disease state and distinguishes ADC eligibility from therapeutic priority. | Passed | Supported |
Antibody-drug conjugates (ADCs) are emerging therapeutic options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) after the development of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs).
Accordingly, ADCs should be positioned relative to competing local and systemic strategies rather than considered a uniform post-osimertinib class.
Antibody-drug conjugates (ADCs) are emerging therapeutic options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) after the development of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs).
This narrative review links agent-specific evidence boundaries to an eight-domain assessment of the post-progression disease state and distinguishes ADC eligibility from therapeutic priority.
Acta Pharmacol Sin, 2026. PMID 42897224. Found by the main search.
In EGFR-mutant non-small cell lung cancer, osimertinib resistance is driven by MMP14-mediated cleavage of LAMC2, which releases a bioactive Domain III fragment containing EGF-like repeats. This fragment reactivates EGFR/AKT/ERK signaling pathways despite continued exposure to the drug.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | MMP14-mediated proteolytic cleavage of LAMC2 domain III fragment | MMP14-mediated proteolytic cleavage of LAMC2 domain III fragment | Passed | Supported |
| context | EGFR-mutant non-small cell lung cancer | EGFR-mutant non-small cell lung cancer | Passed | Supported |
| drug | osimertinib | osimertinib | Passed | Supported |
| setting | Acquired resistance | Acquired resistance | Passed | Supported |
| study type | cell-line study | quantitative secretomic profiling of paired osimertinib-sensitive and -resistant NSCLC cell lines | Passed | Not in the abstract |
| finding type | resistance mechanism | These findings identify the MMP14-LAMC2-DIII proteolytic axis as a non-genetic resistance mechanism | Passed | Supported |
| key finding | MMP14 cleaved LAMC2 to release a bioactive Domain III (DIII) fragment harboring EGF-like repeats, which reactivated EGFR/AKT/ERK signaling despite continued osimertinib exposure. | MMP14 cleaved LAMC2 to release a bioactive Domain III (DIII) fragment harboring EGF-like repeats, which reactivated EGFR/AKT/ERK signaling despite continued osimertinib exposure. | Passed | Supported |
Acquired resistance to osimertinib remains a critical clinical challenge in EGFR-mutant non-small cell lung cancer (NSCLC), with 40%-60% of progressing patients lacking an identifiable genetic resistance driver.
Acquired resistance to osimertinib remains a critical clinical challenge in EGFR-mutant non-small cell lung cancer (NSCLC), with 40%-60% of progressing patients lacking an identifiable genetic resistance driver.
Mechanistically, MMP14 cleaved LAMC2 to release a bioactive Domain III (DIII) fragment harboring EGF-like repeats, which reactivated EGFR/AKT/ERK signaling despite continued osimertinib exposure.
Through quantitative secretomic profiling of paired osimertinib-sensitive and -resistant NSCLC cell lines, we identified laminin subunit γ2 (LAMC2) as markedly enriched in resistant cell secretomes.
Phytomedicine, 2026. PMID 42868834. Found by the main search.
Xanthatin restores osimertinib sensitivity in osimertinib-resistant NSCLC cells by directly binding to HMGCR and promoting its AMFR-mediated K48-linked ubiquitination and subsequent degradation. This mechanism disrupts cholesterol metabolism, reduces MDR1 distribution in lipid rafts, and induces ROS accumulation and mitochondrial dysfunction-associated apoptosis.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | disturbing cholesterol metabolism via targeting HMGCR protein degradation | disturbing cholesterol metabolism via targeting HMGCR protein degradation | Passed | Supported |
| drug | xanthatin | xanthatin | Passed | Supported |
| setting | osimertinib-resistant (OR) NSCLC cells | osimertinib-resistant (OR) NSCLC cells | Passed | Supported |
| study type | in vitro and in vivo experiments | in vitro and in vivo experiments | Passed | Supported |
| finding type | resistance mechanism | Our study demonstrates for the first time that xanthatin directly binds to HMGCR and promotes AMFR-mediated K48-linked ubiquitination of HMGCR, which in turn accelerates HMGCR degradation through the ubiquitin-proteasome pathway, leading to reduced cholesterol synthesis, less distribution of MDR1 in lipid rafts, ROS accumulation, and mitochondrial dysfunction-associated apoptosis, ultimately restoring osimertinib sensitivity in NSCLC cells. | Passed | Supported |
| key finding | xanthatin directly binds to HMGCR and promotes AMFR-mediated K48-linked ubiquitination of HMGCR, which in turn accelerates HMGCR degradation through the ubiquitin-proteasome pathway, leading to reduced cholesterol synthesis, less distribution of MDR1 in lipid rafts, ROS accumulation, and mitochondrial dysfunction-associated apoptosis, ultimately restoring osimertinib sensitivity in NSCLC cells. | xanthatin directly binds to HMGCR and promotes AMFR-mediated K48-linked ubiquitination of HMGCR, which in turn accelerates HMGCR degradation through the ubiquitin-proteasome pathway, leading to reduced cholesterol synthesis, less distribution of MDR1 in lipid rafts, ROS accumulation, and mitochondrial dysfunction-associated apoptosis, ultimately restoring osimertinib sensitivity in NSCLC cells. | Passed | Supported |
Methods: Combenefit analysis, LDH release assay, and EdU staining were employed to evaluate the effect of xanthatin on osimertinib cytotoxicity in osimertinib-resistant (OR) NSCLC cells.
Background: Osimertinib is a third-generation, irreversible EGFR tyrosine kinase inhibitor (TKI), nevertheless, the inevitable occurrence of osimertinib resistance after a long-term administration limits its clinical application in non-small cell lung cancer (NSCLC).
Results: Xanthatin restored the sensitivity of NSCLC OR cells to osimertinib, accompanied by the induction of oxidative stress and mitochondrial dysfunction.
Methods: Combenefit analysis, LDH release assay, and EdU staining were employed to evaluate the effect of xanthatin on osimertinib cytotoxicity in osimertinib-resistant (OR) NSCLC cells.
Eur J Med Chem, 2026. PMID 42868668. Found by the main and second search.
This study addresses acquired osimertinib resistance driven by the EGFRC797S mutation and bypass pathway activation through the design of aminopyrimidine-based small-molecule inhibitors. The lead compound 6a demonstrates potent single-digit nanomolar activity against the EGFRL858R/T790M/C797S triple mutation and equipotent ALK inhibitory activity, potentially addressing ALK-mediated bypass resistance.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | EGFRC797S mutation and bypass pathway activation | EGFRC797S mutation and bypass pathway activation are major drivers of acquired resistance to osimertinib | Passed | Supported |
| variant | EGFRC797S | EGFRC797S mutation | Passed | Supported |
| context | acquired resistance to osimertinib | acquired resistance to osimertinib | Passed | Supported |
| drug | aminopyrimidine-based small-molecule inhibitors | aminopyrimidine-based small-molecule inhibitors | Passed | Supported |
| setting | overcoming osimertinib resistance | overcoming osimertinib resistance | Passed | Supported |
| study type | Design, synthesis and biological evaluation | Design, synthesis and biological evaluation | Passed | Supported |
| finding type | resistance mechanism | EGFRC797S mutation and bypass pathway activation are major drivers of acquired resistance to osimertinib | Passed | Supported |
| key finding | The lead compound 6a exhibits potent single-digit nanomolar activity against EGFRL858R/T790M/C797S (IC50 = 1.76 nM), along with equipotent ALK inhibitory activity (IC50 = 1.95 nM) that may address ALK-mediated bypass resistance. | The lead compound 6a exhibits potent single-digit nanomolar activity against EGFRL858R/T790M/C797S (IC50 = 1.76 nM), along with equipotent ALK inhibitory activity (IC50 = 1.95 nM) that may address ALK-mediated bypass resistance. | Passed | Supported |
In cellular assays, 6a potently inhibits proliferation of osimertinib-resistant H1975-M3 cells (IC50 = 0.035 μM), suppresses downstream oncogenic signaling, induces G0/G1 cell cycle arrest and apoptosis, and impairs cell migration and invasion.
EGFRC797S mutation and bypass pathway activation are major drivers of acquired resistance to osimertinib; however, no approved therapeutic agents are currently available to effectively overcome this resistance.
EGFRC797S mutation and bypass pathway activation are major drivers of acquired resistance to osimertinib; however, no approved therapeutic agents are currently available to effectively overcome this resistance.
In this study, a series of aminopyrimidine-based small-molecule inhibitors were rationally designed and synthesized.
Front Genet, 2026. PMID 42861401. Found by the main and second search.
A bioinformatics screening and in vitro study identified a 7-gene M2 macrophage-associated signature associated with acquired resistance to osimertinib. Among these genes, RRBP1 was highlighted as a potential candidate regulator of this resistance mechanism.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | M2 macrophage-associated gene signature | M2 macrophage-associated gene signature | Passed | Supported |
| drug | Osimertinib | Osimertinib | Passed | Supported |
| setting | acquired resistance | acquired resistance | Passed | Supported |
| study type | bioinformatics screening and in vitro cell experiments | In vitro cell experiments were further performed for functional validation. | Passed | Supported |
| n patients | 6 | 6 NSCLC patients | Passed | Supported |
| finding type | resistance mechanism | our study identified a 7-MORGs signature for OR, among which RRBP1 may be a candidate regulator for OR. | Passed | Supported |
| key finding | our study identified a 7-MORGs signature for OR, among which RRBP1 may be a candidate regulator for OR. | our study identified a 7-MORGs signature for OR, among which RRBP1 may be a candidate regulator for OR. | Passed | Supported |
Methods: To address this gap, a total of 6 lung cancer tissue samples were collected from a cohort of 6 NSCLC patients and subjected to single-cell RNA sequencing (scRNA-seq).
Introduction: Although the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) Osimertinib is widely used in lung adenocarcinoma (LUAD), acquired resistance to this agent remains a major clinical challenge perplexing the academic community.
Conclusion: In summary, our study identified a 7-MORGs signature for OR, among which RRBP1 may be a candidate regulator for OR.
Methods: To address this gap, a total of 6 lung cancer tissue samples were collected from a cohort of 6 NSCLC patients and subjected to single-cell RNA sequencing (scRNA-seq).
Front Oncol, 2026. PMID 42840625. Found by the main search.
This review identifies polygenic methylation as a resistance mechanism to osimertinib in NSCLC. These methylation changes impact drug target mutations, transporter functions, and signaling pathways.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | polygenic methylation | polygenic methylation | Passed | Supported |
| drug | osimertinib | Osimertinib | Passed | Supported |
| study type | review | This review | Passed | Supported |
| finding type | resistance mechanism | This review summarizes the role of polygenic methylation in osimertinib resistance in NSCLC | Passed | Supported |
| key finding | Changes in polygenic methylation patterns are linked to osimertinib resistance in NSCLC, affecting drug target mutations, transporter functions, and signaling pathways. | Changes in polygenic methylation patterns are linked to osimertinib resistance in NSCLC, affecting drug target mutations, transporter functions, and signaling pathways. | Passed | Supported |
Osimertinib, a third-generation EGFR-TKI, is effective for non-small cell lung cancer (NSCLC), but drug resistance significantly worsens patient outcomes.
Osimertinib, a third-generation EGFR-TKI, is effective for non-small cell lung cancer (NSCLC), but drug resistance significantly worsens patient outcomes.
Changes in polygenic methylation patterns are linked to osimertinib resistance in NSCLC, affecting drug target mutations, transporter functions, and signaling pathways.
This review summarizes the role of polygenic methylation in osimertinib resistance in NSCLC, examining its effects on drug targets, transporter functions, and signaling pathways.
Front Oncol, 2026. PMID 42835192. Found by the main search.
A biochemical and cellular profiling study compared the activity of osimertinib with three fourth-generation EGFR inhibitors (BLU-945, JBJ-09-063, and silevertinib) in the context of resistance driven by the EGFR C797S mutation. The analysis revealed substantial differences in the activity landscapes among these fourth-generation inhibitors.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | EGFR C797S mutation | Clinical resistance to osimertinib frequently arises through the EGFR C797S mutation | Passed | Supported |
| variant | EGFR C797S mutation | EGFR C797S mutation | Passed | Supported |
| context | resistance to osimertinib | Clinical resistance to osimertinib | Passed | Supported |
| drug | osimertinib and three fourth-generation EGFR inhibitors: BLU-945, JBJ-09-063 and silevertinib | osimertinib and three fourth-generation EGFR inhibitors: BLU-945, JBJ-09-063 and silevertinib | Passed | Supported |
| study type | biochemical and cellular profiling | side-by-side biochemical and cellular profiling | Passed | Supported |
| finding type | other | This comparative analysis highlights the substantial differences in the activity landscapes of fourth-generation EGFR inhibitors. | Passed | Supported |
| key finding | This comparative analysis highlights the substantial differences in the activity landscapes of fourth-generation EGFR inhibitors. | This comparative analysis highlights the substantial differences in the activity landscapes of fourth-generation EGFR inhibitors. | Passed | Supported |
Effects on cell viability were evaluated in a CRISPR-engineered NCI-H1975 cell line harboring L858R + T790M + C797S and across a 113 cancer cell line panel including ten EGFR-mutant cell lines, harboring mutations other than C797S.
Methods: We performed side-by-side biochemical and cellular profiling of osimertinib and three fourth-generation EGFR inhibitors: BLU-945, JBJ-09-063 and silevertinib.
Effects on cell viability were evaluated in a CRISPR-engineered NCI-H1975 cell line harboring L858R + T790M + C797S and across a 113 cancer cell line panel including ten EGFR-mutant cell lines, harboring mutations other than C797S.
Methods: We performed side-by-side biochemical and cellular profiling of osimertinib and three fourth-generation EGFR inhibitors: BLU-945, JBJ-09-063 and silevertinib.
Clin Lung Cancer, 2026. PMID 42837955. Found by the second search.
A global survey-based chart review of 367 patients with acquired MET OverExp/Amp after progression on first-line osimertinib found that rebiopsy practices and knowledge of MET OverExp/Amp cutoffs varied among physicians. The study examined second-line treatment options, including MET-TKIs, EGFR-TKIs, and chemotherapy.
Written by groq/qwen/qwen3.8-27b from the extracted fields only. It never saw the abstract.
| Field | Extracted value | Quote from the paper | Code check | Second model |
|---|---|---|---|---|
| mechanism | acquired MET OverExp/Amp | acquired MET OverExp/Amp | Passed | Supported |
| variant | MET OverExp/Amp | MET OverExp/Amp | Passed | Supported |
| context | after progression on first-line osimertinib | after progression on first-line osimertinib | Passed | Supported |
| drug | MET-TKIs, EGFR-TKIs, chemotherapy | MET-TKIs (29%) and EGFR-TKIs (24%) were the most common second-line treatments, followed by chemotherapy (20%) | Passed | Supported |
| setting | second-line treatment | received second-line treatment | Passed | Supported |
| study type | global, direct-to-physician, survey-based chart review | global, direct-to-physician, survey-based chart review | Passed | Supported |
| n patients | 367 | Among 367 patients | Passed | Supported |
| finding type | other | Rebiopsy practices and knowledge of MET OverExp/Amp cutoffs varied among physicians. | Passed | Not in the abstract |
| key finding | Rebiopsy practices and knowledge of MET OverExp/Amp cutoffs varied among physicians. | Rebiopsy practices and knowledge of MET OverExp/Amp cutoffs varied among physicians. | Passed | Supported |
Biomarker testing, MET OverExp/Amp quantification and treatment sequencing were assessed in patients with EGFR-mutated advanced NSCLC with acquired MET OverExp/Amp after progression on first-line osimertinib, who received second-line treatment between January 2018 and December 2023 (data cutoff: April 8, 2025).
Biomarker testing, MET OverExp/Amp quantification and treatment sequencing were assessed in patients with EGFR-mutated advanced NSCLC with acquired MET OverExp/Amp after progression on first-line osimertinib, who received second-line treatment between January 2018 and December 2023 (data cutoff: April 8, 2025).
Biomarker testing, MET OverExp/Amp quantification and treatment sequencing were assessed in patients with EGFR-mutated advanced NSCLC with acquired MET OverExp/Amp after progression on first-line osimertinib, who received second-line treatment between January 2018 and December 2023 (data cutoff: April 8, 2025).
We report findings from a global, direct-to-physician, survey-based chart review.
The main search found 21 relevant papers and the second, independently built search found 14. 9 were found by both. That overlap puts the total number of relevant papers at about 32 (range 26 to 40). Together the searches found 26, so about 6 relevant papers were likely missed by both.
Assumes the two searches find papers independently. They are built from different terms for that reason, but some dependence remains, which makes the estimate a lower bound.
These are confirmed misses of the main search, and candidates for improving its query.
A random sample of what screening threw out. Every wrong exclusion found here is a measured miss, and becomes a test case.
(EGFR[tiab] OR "ErbB Receptors"[mh]) AND (osimertinib[tiab] OR AZD9291[tiab] OR Tagrisso[tiab]) AND resistan*[tiab]("Drug Resistance, Neoplasm"[mh] OR "acquired resistance"[tiab] OR "disease progression"[tiab] OR progressed[tiab]) AND ("third-generation"[tiab] OR "third generation"[tiab] OR T790M[tiab] OR C797S[tiab] OR "EGFR-TKI"[tiab] OR "EGFR TKI"[tiab]) AND (NSCLC[tiab] OR "lung cancer"[tiab] OR "lung adenocarcinoma"[tiab])| PMID | SHA-256 of the abstract |
|---|---|
| 42919317 | 3f9ce63a08dfd144 |
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| 42897224 | 90a2ea85c2dfa320 |
| 42882792 | 978c4686c59a7b82 |
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| 42861401 | 045025dc5faae03d |
| 42849656 | d883dd387d29f255 |
| 42846034 | 2c55cee0d869f9ac |
| 42840625 | 11cde753648802eb |
| 42835192 | dd65e2c4f157b377 |
| 42833236 | 3179c5b869e55bfb |
| 42810632 | a2c1d120ec7a1742 |
| 42806046 | 905a7a0e0ae752e0 |
| 42804885 | e37ff857ccb842c3 |
| 42792909 | 71e7152b64f59a6e |
| 42899412 | eb6395fa3c049c95 |
| 42888981 | 3f4ecceb2452a0c6 |
| 42887461 | 479a1245f6a1500f |
| 42877579 | 4bdd5e6e4ee35267 |
| 42870929 | eddb925d1fb031ef |
| 42870834 | 266cefaf3b4be9ac |
| 42870814 | 106df16733cf670a |
| 42839779 | 7ccc516d2fc94cb0 |
| 42837955 | ebe77f033d43f78c |
| 42833237 | e3b0c44298fc1c14 |
| 42818644 | 33261c6cceaf205f |
| 42817873 | ec88f36c7930a36c |
| 42799075 | dfbbeaa7ee4ee182 |
| 42793623 | 2cff8d6da110a70d |
The full record, including every model answer, is in run.json next to this page.