Concurrent Alterations in EGFR-Mutant Lung Cancers Associated with Resistance to EGFR Kinase Inhibitors and Characterization of MTOR as a Mediator of Resistance
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Abstract
Abstract Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR-mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing. Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR-mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies. Results: In 200 EGFR-mutant pretreatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1, and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1. Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR = 2.4, P = 0.015) or MET (HR = 3.7, P = 0.019), or mutation in TP53 (HR = 1.7, P = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%), and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo. Conclusions: EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. Clin Cancer Res; 24(13); 3108–18. ©2018 AACR.
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NRF2-activating mutations have been associated with chemo- and radiation resistance in lymphoma, leukemia, and solid tumors.
“NRF2-activating mutations are rare in untreated lymphomas; however, they have been associated with chemo- and radiation resistance in lymphoma [37,38], leukemia [39], and in solid tumors [40].”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [40]
The Discussion (page unavailable) links KEAP1 loss and increased NRF2 expression to possible resistance to RTK/MAPK pathway inhibitors in non-small-cell lung cancer. Citation [40] is attached to the solid-tumor portion of the citing sentence, but the source does not establish resistance to chemotherapy or radiation, or address NRF2-activating mutations specifically. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSeveral distinct patterns of co-mutations are enriched in metastatic disease, likely reflecting acquisition of traits that promote tumor progression and metastatic dissemination.
“In particular, it is critical to distinguish between early-stage, surgically resected tumors and locally advanced or metastatic disease because several distinct patterns of co-mutations are enriched in metastatic disease, likely reflecting acquisition of traits that promote tumor progression and metastatic dissemination72, 73.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
The spectrum of enriched genomic co-alterations in advanced EGFR-mutant LUAD is dominated by recurrent mutations in TP53 (54.6%-64.6%), RB1 (9.6%-10.33%), CTNNB1 (5.3%-9.6%), and PIK3CA (9%-12.4%), as well as amplifications involving EGFR (22%-25.5%), NKX2-1 (12.2%-16.7%), CDK4 (7%-10%), CDK6 and CCNE1.
“The spectrum of enriched genomic co-alterations in advanced EGFR-mutant LUAD is dominated by recurrent mutations in a core set of genes including TP53 (54.6% % - 64.6%), RB1 (9.6%−10.33%), CTNNB1 (which encodes β-catenin; 5.3%−9.6%), and PIK3CA (9%−12.4%) as well as amplifications involving EGFR itself (22% - 25.5%), NKX2–1 (12.2% - 16.7%), CDK4 (7%−10%), CDK6 and CCNE115, 72, 73 (Figure 2).”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
Mutations in PIK3CA and CTNNB1 are more frequent in advanced stage tumors compared with early stage LUADs, whereas alterations in TP53, RB1 and NKX2-1 appear to occur with comparable frequencies in early- and advanced-stage tumors.
“Mutations in PIK3CA and CTNNB1 are more frequent in advanced stage tumors compared with early stage LUADs, pointing towards functional roles in malignant progression and metastasis, whereas alterations in TP53 (62.5%), RB1 (9.5 −12.5%) and NKX2–1 (12.5%) appear to occur with comparable frequencies in early- and advanced-stage tumors15, 34, 72, 73.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
The overwhelming majority of EGFR-mutant lung tumors harbor one or more co-mutations, even when analysis is limited to pre-defined sets of cancer-relevant genes within established panels.
“Although EGFR –mutant tumors represent the prototypical oncogene-addicted LUAD subgroup that spearheaded adoption of the single-driver model, the overwhelming majority of EGFR-mutant lung tumors harbor one or more co-mutations, even when the analysis is limited to pre-defined sets of cancer-relevant genes within established panels (FoundationOne, Guardant360, MSK-IMPACT)15, 59, 72, 73.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
Multiple clinical studies have identified TP53 co-alterations as a negative prognostic marker in EGFR-mutant LUAD and a consistent predictor of worse clinical outcomes following EGFR TKI therapy.
“In keeping with a more complex genomic landscape and a larger burden of clonal or sub-clonal co-drivers, multiple clinical studies have identified TP53 co-alterations as a negative prognostic marker in EGFR-mutant LUAD and a consistent predictor of worse clinical outcomes following EGFR TKI therapy72, 73, 111–116.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%-12.5% of EGFR-mutant LUAD.
“Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%−12.5% of EGFR-mutant LUAD72, 73, 103, 117.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
PIK3CA kinase and helical domain mutations occur in 9%-12.4% of advanced-stage EGFR-mutant LUAD.
“PIK3CA mutations, including classical kinase (H1074R and H1074L) and helical (E545K and E542K) domain mutations are observed in 9%−12.4% of advanced stage EGFR-mutant LUAD”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
EGFR and CTNNB1 co-mutated NSCLC cells show increased invasive potential in vitro.
“experimental data demonstrating increased invasive potential of EGFR and CTNNB1 co-mutated NSCLC cells in vitro15, 34, 72, 73, 120, 121”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
CTNNB1 mutation prevalence rises in late-stage EGFR-mutant LUAD to 5.3%-9.6%.
“their prevalence increases in late-stage tumors (5.3% - 9.6%)”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
Activating CTNNB1 mutations are among the most consistently co-selected alterations in EGFR-mutant LUAD across studies.
“Activating mutations in CTNNB1 represent one of the most consistently co-selected alterations in EGFR-mutant LUAD across different studies.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
WNT signaling has a central role in LUAD metastasis.
“earlier studies that identified a central role for WNT signaling in LUAD metastasis”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
Genomic alterations, most commonly deletion events, in CDKN2A and CDKN2B are observed in ~24.6% and 20.2% of EGFR-mutant tumors and these alterations are typically truncal.
“Similarly, genomic alterations –most commonly deletion events - in the CDKN2A and CDKN2B genes are observed in ~24.6% and 20.2% of EGFR-mutant tumors and these alterations are typically truncal, further underscoring the significance of G1/S checkpoint dysregulation in the early stages of lung carcinogenesis driven by mutant EGFR72, 73, 103.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
PIK3CA mutations are preferentially found in advanced-stage tumors.
“like CTNNB1 mutations, are encountered preferentially in advanced-stage tumors15, 34, 72, 73”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
Evidence also indicates that TP53 co-mutations worsen outcomes on third-generation mutant-selective EGFR TKIs in patients with acquired EGFR T790M.
“there is further evidence that they adversely impact clinical outcomes with the third generation, mutant-selective EGFR TKIs, in patients whose tumors have acquired the EGFRT790M gatekeeper mutation72, 115.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
In a separate cohort with acquired EGFR T790M, RB1 and PTEN co-mutations plus MDM2 amplification independently predicted poorer PFS on third-generation EGFR TKIs.
“among patients with acquired EGFRT790M mutation from a distinct cohort, co-mutations in RB1 and PTEN and amplification of MDM2 were independently associated with worse progression-free survival following treatment with 3rd generation EGFR TKIs72, 173.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
Among 200 EGFR-mutant patients, baseline MET amplification (2%) predicted markedly shorter PFS on first-line first- or second-generation EGFR TKIs.
“In a study of 200 EGFR-mutant patients with extensive molecular profiling at baseline, pre-existing MET (present in 2% of cases) or ERBB2 (4% prevalence) amplification were also associated with significantly shorter progression-free survival with first-line 1st or 2nd generation EGFR TKI therapy”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
Across studies, TP53 co-mutations predict shorter PFS when first- or second-generation EGFR TKIs are given upfront.
“TP53 co-mutations have consistently been associated with shorter progression-free survival following upfront treatment with 1st or 2nd generation EGFR TKIs”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
In that same cohort, baseline ERBB2 amplification (4%) also predicted markedly shorter PFS on first-line first- or second-generation EGFR TKIs.
“In a study of 200 EGFR-mutant patients with extensive molecular profiling at baseline, pre-existing MET (present in 2% of cases) or ERBB2 (4% prevalence) amplification were also associated with significantly shorter progression-free survival with first-line 1st or 2nd generation EGFR TKI therapy”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [72]
The specific co-occurring alterations that affect third-generation EGFR-TKI outcomes beyond primary driver mutations are largely unknown.
“However, specific co-occurring genetic alterations that affect the clinical outcomes of EGFR-TKI 3rd in addition to primary driver mutations remain largely unknown.12”
From Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC (2019) · cites this paper as [12]
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Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin
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Mutations of p53 and K-ras genes as prognostic factors for non-small cell lung cancer.
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Flagged first, then by citations
Research works printed but not linked: 1
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Cited by
Sorted by citations
Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
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The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase
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Cell signaling and cancer: a mechanistic insight into drug resistance
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NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
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“NRF2‐activating mutations are rare in untreated lymphomas; however, they have been associated with chemo‐ and radiation resistance in lymphoma [37,38], leukemia [39], and in solid tumors [40].”
BackgroundCuadrado, A., Cazalla, E., Bach, A., Bathish, B., Naidu, S. D., DeNicola, G. M., Dinkova-Kostova, A. T., Fernández-Ginés, R., Grochot-Przeczek, A., Hayes, J. D., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103569 · Cited by 28 · see citing works
- Authors
- Yu, H. A., Suzawa, K., Jordan, E., Zehir, A., Ni, A., Kim, R., Kris, M. G., Hellmann, M. D., Li, B. T., Somwar, R., Solit, D. B., Berger, M. F., Arcila, M., Riely, G. J., & Ladanyi, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- 3Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
- Corresponding author
- Yu, Helena A.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2018-07-01
- Volume
- 24
- Issue
- 13
- Pages
- 3108-3118
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC6420806
- OpenAlex
- W2792218462
- Cited by
- 259
- References
- 55
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 25 · 2023: 29 · 2022: 37 · 2021: 43 · 2020: 42 · 2019: 42 · 2018: 8
- FWCI
- 25.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (P01 CA129243)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- EGFR-mutant lung cancer, EGFR tyrosine kinase inhibitors, acquired drug resistance, erlotinib resistance, MET amplification, ERBB2 amplification, TP53 mutation, T790M mutation, BRAF fusion, FGFR3 fusion, time to progression
- MeSH terms
- Antineoplastic Agents, Humans, Lung Neoplasms, Mutation, Prognosis, Biomarkers, Tumor, Drug Resistance, Neoplasm, Genomics, Cell Line, Tumor, Protein Kinase Inhibitors, TOR Serine-Threonine Kinases, ErbB Receptors
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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