Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors

Sequist, Lecia V.; Waltman, Belinda A.; Dias-Santagata, Dora; Digumarthy, Subba; Turke, Alexa B.; Fidias, Panos; Bergethon, Kristin; Shaw, Alice T.; Gettinger, Scott; Cosper, Arjola K.; Akhavanfard, Sara; Heist, Rebecca S.; Temel, Jennifer; Christensen, James G.; Wain, John C.; Lynch, Thomas J.; Vernovsky, Kathy; Mark, Eugene J.; Lanuti, Michael; Iafrate, A. John; Mino-Kenudson, Mari; Engelman, Jeffrey A.

doi:10.1126/scitranslmed.3002003

Cited by 3,499Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors

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Sequist, Lecia V., Waltman, Belinda A., Dias-Santagata, Dora, Digumarthy, Subba, Turke, Alexa B., Fidias, Panos, Bergethon, Kristin, Shaw, Alice T. +14 more·2011·Science Translational Medicine

DOI 10.1126/scitranslmed.3002003PMC PMC3132801

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Abstract

Lung cancers undergo dynamic genetic and histological changes upon developing resistance to EGFR inhibitors.

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Crossref · 10.1126/scitranslmed.3002003

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The T790M mutation is a well-characterized mechanism of acquired resistance to first- and second-generation TKIs, reported to occur in >60% of cases.
“The “gatekeeper” T790M mutation is a well-characterized mechanism of acquired resistance to first- and second-generation TKIs, which has been reported to occur in >60% of cases.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [45]
The Results (Genotypic mechanisms of acquired drug resistance; page unavailable) identify T790M as an acquired resistance mechanism, but report it in 18 of 37 patients (49%), not more than 60%. The Discussion (page unavailable) calls 49% consistent with previously reported incidence. It discusses possible resistance to newer irreversible inhibitors, but does not establish the claimed frequency for first- and second-generation TKIs together. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Acquired resistance to EGFR TKIs occurs in the majority of patients after first-line treatment of EGFRm+ NSCLC.
“Despite the efficacy of EGFR TKIs in the first-line treatment of EGFRm+ NSCLC, acquired resistance to therapy occurs in the majority of patients.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [45]
The Introduction says most EGFR-mutant NSCLCs initially respond to EGFR TKIs but subsequently acquire resistance, and the Discussion describes resistance as occurring after about 12 months of treatment. The paper does not establish that a majority acquire resistance specifically after first-line treatment; its Discussion mentions only two first-line erlotinib cases separately. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
The most common mechanism of resistance to first-generation EGFR TKIs is T790M, occurring in approximately 50-70% of patients.
“The most common mechanism of resistance to first-generation EGFR TKIs is the development of the gatekeeper T790M mutation, which occurs in approximately 50–70% of patients.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [45]
The Results (Genotypic mechanisms of acquired drug resistance) report T790M in 18 of 37 patients (49%), more than any other identified mechanism. The Introduction also describes T790M in about half of resistant cancers, but the paper does not establish the claimed 50–70% range. (LLM, conf=0.85)
Experimental — accuracy not yet measured
In two NSCLC patients without an identified genomic resistance mechanism, histologic transformation from adenocarcinoma to squamous-cell carcinoma was observed, suggesting nongenetic mechanisms of resistance to KRASG12C inhibition may occur.
“In two patients with NSCLC for whom we were not able to identify a genomic resistance mechanism, we observed histologic transformation from adenocarcinoma to squamous-cell carcinoma, which suggests that nongenetic mechanisms of resistance to KRASG12C inhibition may occur, similar to those observed with other targeted therapies in lung cancer.24-26”
From Acquired Resistance to KRAS G12C Inhibition in Cancer (2021) · cites this paper as [25]
After using first-generation EGFR TKIs for approximately 9-14 months, almost all tumors progressed again.
“after using first-generation EGFR TKIs for approximately 9–14 months, almost all tumors progressed again.111”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [111]

The EGFR T790M gatekeeper mutation is a leading cause of resistance to first- and second-generation EGFR inhibitors in EGFR-mutant lung cancers.
“the EGFR T790M gatekeeper mutation, is a leading cause of resistance to first- and second-generation EGFR inhibitors [11,12].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [12]
Histologic transformation of lung adenocarcinoma to small cell carcinoma accounts for 5-15% of EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs.
“the histologic transformation of lung adenocarcinoma subtype to small cell carcinoma subtype, which accounts for 5–15% of EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs [12,17].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [12]
MET activation accounts for 5-10% of lung cancer resistance to EGFR TKIs.
“MET activation, by either gene amplification or ligand stimulation, accounts for 5–10% of lung cancer resistance to EGFR TKIs [12,14].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [12]
Similar phenomenon occurs in other targeted therapies for lung cancer.
“Similar phenomenon occurs in other targeted therapies for lung cancer [94, 140, 141].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [141]
Genomic sequencing of EGFR from both baseline and repeated biopsy samples shows that a transformed SCLC tumour sample retained the original EGFR-activating mutation, suggesting that these were not de novo clones, but rather a transformed phenotype of pre-existing cancer cells.
“Genomic sequencing of EGFR from both the baseline and repeated biopsy samples shows that a transformed SCLC tumour sample retained the original EGFR-activating mutation, suggesting that these were not de novo clones, but rather a transformed phenotype of pre-existing cancer cells.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [34]
Repeated bioptic sampling from patients with EGFR-mutant NSCLCs has shown a rare but consistent observation of histological transformation from adenocarcinoma to small cell lung cancer (SCLC).
“Repeated bioptic sampling from patients with EGFR-mutant NSCLCs have shown a rare but consistent observation of histological transformation from adenocarcinoma to small cell lung cancer (SCLC).34”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [34]
Patients with adenocarcinoma-SCLC transformation presented mixed responses to EGFR inhibitors, despite the persistency of the activating mutation, probably due to the loss of EGFR expression at the protein level.
“However, patients with adenocarcinoma-SCLC transformation presented mixed responses to EGFR inhibitors, despite the persistency of the activating mutation, probably due to the loss of EGFR expression at the protein level.34”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [34]
Activation of other cell receptors such as FGFR1,2,3 or of cell signalling pathways such as BRAF (Val600Glu, Gly469Ala) mutation (1%) and PIK3CA mutation (5%), that play a key role in promoting the proliferation, survival, drug resistance of cancer cells, have been described.
“Activation of other cell receptors such as FGFR1,2,351 or of cell signalling pathways such as BRAF (Val600Glu, Gly469Ala) mutation (1%)52 and PIK3CA mutation (5%)34, that play a key role in promoting the proliferation, survival, drug resistance of cancer cells, have been described.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [34]
T790M is the most common acquired resistance mechanism in EGFR-mutant adenocarcinomas that progress on erlotinib, occurring in more than half of resistant biopsies.
“A secondary epidermal growth factor receptor (EGFR) mutation, T790M, is the most common resistance mechanism in EGFR mutant adenocarcinomas that have progressed on erlotinib.”
From The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies (2015) · cites this paper as [14]
EGFR mutant SCLCs are highly sensitive to SCLC chemotherapy regimens.
“These data are further supported by the clinical observations that EGFR mutant SCLCs are highly sensitive to SCLC chemotherapy regimens7.”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [7]
A subset of resistant EGFR mutant non-small-cell lung cancers undergo histological transformation to small-cell lung cancer.
“A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [7]
All resistant SCLC cancers harboured the original activating EGFR mutation.
“As reported previously, all of the resistant SCLC cancers harboured the original activating EGFR mutation7.”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [7]
The SCLC transformed tumours harboured the original activating EGFR mutation, suggesting direct evolution from the initial cancer rather than a distinct second primary cancer.
“Importantly, the tumours that transformed to SCLC harboured the original activating EGFR mutation, suggesting direct evolution from the initial cancer, rather than a distinct, second primary cancer.”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [7]
Both SCLC transformed samples harboured an activating mutation in PIK3CA.
“Both SCLC transformed samples harboured an activating mutation in PIK3CA, which we previously observed in SCLC transformed cases7”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [7]
Repeat biopsy studies have consistently suggested that SCLC transformed cancers represent an evolution from the initial adenocarcinomas rather than a second coincident cancer, because the activating driver EGFR mutations are identical to the original adenocarcinomas in all cases.
“However, repeat biopsy studies have consistently suggested that the SCLC transformed cancers represent an evolution from the initial adenocarcinomas rather than a second coincident cancer, because the activating driver EGFR mutations are identical to the original adenocarcinomas in all cases.”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [7]
5-15% of patient tumours undergo transformation to SCLC histology upon acquisition of resistance.
“One unexpected finding from these studies was the discovery that 5–15% of patient tumours undergo transformation to SCLC histology upon acquisition of resistance.”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [7]
It is unlikely that these SCLCs were present from the onset of the disease in a majority of these cases because when the SCLC surfaces in the clinic, it progresses quite rapidly.
“However, from a clinical perspective, we feel that it is unlikely that these SCLCs were present from the onset of the disease in a majority of these cases because when the SCLC surfaces in the clinic, it progresses quite rapidly (like classical SCLC)7.”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [7]
The T790M EGFR mutation is present in approximately 50 to 60% of cases of acquired resistance to EGFR inhibitors.
“is most commonly due to the EGFR T790M mutation, present in approximately 50 to 60% of resistant cases.5,6”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [5]
EMT has been indicated as one mechanism of resistance to EGFR-TKIs.
“Epithelial‐mesenchymal transition (EMT) has also been indicated as one mechanism of resistance to EGFR-TKIs[10].”
From Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR -Mutant NSCLC (2018) · cites this paper as [10]
At progression, about 60% of patients have T790M mutation in EGFR.
“At the time of progression, about 60% of patients (regardless of race or ethnic background) are found to have a p.Thr790Met point mutation (T790M) in the gene encoding EGFR.13–16”
From Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer (2017) · cites this paper as [15]
Acquired resistance to conventional EGFR-TKIs develops after a median of 10 to 12 months and is most commonly mediated by an acquired T790M mutation.
“Resistance to conventional EGFR-TKIs develops after a median of 10 to 12 months and is most commonly mediated by an acquired mutation, T790M1-5.”
From Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer (2016) · cites this paper as [4]
The EGFR T790M somatic mutation is the most frequent alteration found in about half of tumors that progress on first- or second-generation EGFR TKIs.
“with the EGFR T790M somatic mutation being the most frequent alteration detected in approximately half of progressing tumors.[14][15][16]”
From The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016 (2016) · cites this paper as [14]
Other resistance mechanisms include MET amplification (5-30%), HER2 amplification (12%), PIK3CA mutation (5%), and BRAF mutation (1%).
“Other resistance mechanisms involve bypass pathways such as MET proto-oncogene, receptor tyrosine kinase gene (MET) amplification (5%-30% depending on thresholds), erb-b2 receptor tyrosine kinase 2 (HER2) amplification (12%), phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation (5%), and B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) mutation (1%)”
From The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016 (2016) · cites this paper as [14]
The T790M mutation is the most common finding in EGFR-mutated tumours that relapse after first- or second-generation EGFR TKI therapy.
“the most common finding in EGFR-mutated tumours relapsing after first-/secondgeneration EGFR TKI therapy [19].”
From Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2016) · cites this paper as [19]
Primary EGFR sensitizing mutations are early truncal events, and prior work found little heterogeneity across multiple biopsies.
“each initial EGFR sensitizing mutation is an early “truncal” event in the pathogenesis of lung adenocarcinoma, and previous studies have not detected significant heterogeneity across multiple biopsies (5,37).”
From Detection of T790M, the Acquired Resistance EGFR Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses (2016) · cites this paper as [5]
Genomic heterogeneity within tumors and across metastatic tumor sites in the same patient is the major cause of treatment failure and emergence of therapy resistance.
“Genomic heterogeneity within tumors and across metastatic tumor sites in the same patient is the major cause of treatment failure and emergence of therapy resistance (19).”
From Radiomics: Images Are More than Pictures, They Are Data (2016) · cites this paper as [19]
PIK3CA mutations have been identified in biopsies of EGFR mutant cancers with acquired resistance to EGFR inhibitors.
“Accordingly, PIK3CA mutations have been identified in biopsies of EGFR mutant cancers with acquired resistance to EGFR inhibitors (Sequist et al., 2011).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Sequist et al., 2011

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Dias-Santagata, D. C., Akhavanfard, S., David, S. S., Vernovsky, K., Kuhlmann, G., Boisvert, S. L., Stubbs, H., McDermott, U., Settleman, J. E., Kwak, E. L., et al. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000070 · Cited by 392 · see citing works
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Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer
Regales, L., Gong, Y., Shen, R., de Stanchina, E., Vivanco, I., Goel, A. J., Koutcher, J. A., Spassova, M. K., Ouerfelli, O., Mellinghoff, I. K., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38746 · Cited by 371 · see citing works
Gefitinib Induces Apoptosis in the EGFRL858R Non–Small-Cell Lung Cancer Cell Line H3255
Tracy, S. I., Mukohara, T., Hansen, M., Meyerson, M. M., Johnson, B. E., & Janne, P. A. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1905 · Cited by 368 · see citing works
Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition
Faber, A. C., Li, D., Song, Y., Liang, M., Yeap, B. Y., Bronson, R. T., Lifshits, E., Zhao, C., Maira, S.-M., Garcı́a-Echeverrı́a, C., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905056106 · Cited by 315 · see citing works
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Differential Effects of Gefitinib and Cetuximab on Non–small-cell Lung Cancers Bearing Epidermal Growth Factor Receptor Mutations
Mukohara, T., Engelman, J. A., Hanna, N. H., Yeap, B. Y., Kobayashi, S. S., Lindeman, N. I., Halmos, B., Pearlberg, J., Tsuchihashi, Z., Cantley, L. C., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji238 · Cited by 313 · see citing works
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Epithelial-to-Mesenchymal Transition and Integrin-Linked Kinase Mediate Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Hepatoma Cells
Fuchs, B. C., Fujii, T., Dorfman, J. D., Goodwin, J. M., Zhu, A. X., Lanuti, M. D., & Tanabe, K. K. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-2460 · Cited by 308 · see citing works
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Crosstalk to Stromal Fibroblasts Induces Resistance of Lung Cancer to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Wang, W., Li, Q., Yamada, T., Matsumoto, K., Matsumoto, I., Oda, M., Watanabe, G., Kayano, Y., Nishioka, Y., Sone, S., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1001 · Cited by 297 · see citing works
Prospective Assessment of Discontinuation and Reinitiation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Everolimus
Riely, G. J., Kris, M. G., Zhao, B., Akhurst, T. J., Milton, D. T., Moore, E., Tyson, L. B., Pao, W. J., Rizvi, N. A., Schwartz, L. H., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0560 · Cited by 288 · see citing works
Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non–small cell lung carcinoma
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EGFR Mutations in Small-Cell Lung Cancers in Patients Who Have Never Smoked
Zakowski, M. F., Ladanyi, M., & Kris, M. G. (2006) · New England Journal of Medicine · doi:10.1056/nejmc053610 · Cited by 254 · see citing works
Integrative Genomic and Proteomic Analyses Identify Targets for Lkb1-Deficient Metastatic Lung Tumors
Carretero, J., Shimamura, T., Rikova, K., Jackson, A. L., Wilkerson, M. D., Borgman, C. L., Buttarazzi, M., Sanofsky, B. A., McNamara, K. L., Brandstetter, K. A., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.04.026 · Cited by 243 · see citing works
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Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor
Ercan, D., Zejnullahu, K., Yonesaka, K., Xiao, Y., Capelletti, M., Rogers, A. M., Lifshits, E., Brown, A., Lee, C., Christensen, J. G., et al. (2010) · Oncogene · doi:10.1038/onc.2009.526 · Cited by 229 · see citing works
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Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line
Rho, J. K., Choi, Y. J., Lee, J. K., Ryoo, B., Na, I. I., Yang, S. H., Kim, C. H., & Lee, J. C. (2008) · Lung Cancer · doi:10.1016/j.lungcan.2008.05.017 · Cited by 220 · see citing works
Epidermal Growth Factor Receptor Mutations in Small Cell Lung Cancer
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Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR-TKIs
Chung, J.-H., Rho, J. K., Xu, X., Lee, J. S., Yoon, H. I., Lee, C. T., Choi, Y. J., Kim, H.-R., Kim, C. H., & Lee, J. C. (2010) · Lung Cancer · doi:10.1016/j.lungcan.2010.11.011 · Cited by 186 · see citing works
Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma.
Uramoto, H., Iwata, T., Onitsuka, T., Shimokawa, H., Hanagiri, T., & Oyama, T. (2010) · PubMed · Cited by 168 · see citing works
The P16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung
Beasley, M. B., Lantuéjoul, S., Abbondanzo, S. L., Chu, W., Hasleton, P. S., Travis, W. D., & Brambilla, E. (2003) · Human Pathology · doi:10.1053/hupa.2003.8 · Cited by 157 · see citing works
Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA)
Kokubo, Y., Gemma, A., Noro, R., Seike, M., Kataoka, K., Matsuda, K., Okano, T., Minegishi, Y., Yoshimura, A., Shibuya, M., et al. (2005) · British Journal of Cancer · doi:10.1038/sj.bjc.6602559 · Cited by 137 · see citing works
Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non–Small Cell Lung Cancer Cell Lines
Coldren, C. D., Helfrich, B. A., Witta, S. E., Sugita, M., Lapadat, R., Zeng, C., Barón, A., Franklin, W. A., Hirsch, F. R., Geraci, M. W., et al. (2006) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-06-0095 · Cited by 136 · see citing works
Acquired Resistance to Erlotinib in A-431 Epidermoid Cancer Cells Requires Down-regulation of MMAC1/PTEN and Up-regulation of Phosphorylated Akt
Yamasaki, F., Johansen, M. J., Zhang, D., Krishnamurthy, S., Felix, E. A., Bartholomeusz, C., Aguilar, R. J., Kurisu, K., Mills, G. B., Hortobágyi, G. N., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3020 · Cited by 119 · see citing works
Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation
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EGFR mutation in gefitinib-responsive small-cell lung cancer
Okamoto, I., Araki, J., Suto, R., Shimada, M., Nakagawa, K., & Fukuoka, M. (2005) · Annals of Oncology · doi:10.1093/annonc/mdj114 · Cited by 108 · see citing works
Hepatocyte Growth Factor Reduces Susceptibility to an Irreversible Epidermal Growth Factor Receptor Inhibitor in EGFR -T790M Mutant Lung Cancer
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Retreatment of Lung Adenocarcinoma Patients With Gefitinib Who Had Experienced Favorable Results From Their Initial Treatment With This Selective Epidermal Growth Factor Receptor Inhibitor: A Report of Three Cases
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Epidermal growth factor receptor mutation status and clinicopathological features of combined small cell carcinoma with adenocarcinoma of the lung
Fukui, T., Tsuta, K., Furuta, K., WATANABE, S.-I. I., Asamura, H., Ohe, Y., Maeshima, A. M., Shibata, T., Masuda, N., & Matsuno, Y. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00600.x · Cited by 83 · see citing works
Modeling oncogene addiction using RNA interference
Rothenberg, S. M., Engelman, J. A., Le, S., Riese, D. J., Haber, D. A., & Settleman, J. E. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803217105 · Cited by 47 · see citing works
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Efficacy and safety of PF-00299804 (PF299) in patients (pt) with advanced NSCLC after failure of at least one prior chemotherapy regimen and prior treatment with erlotinib (E): A two-arm, phase II trial
Janne, P. A., Reckamp, K. L., Koczywas, M., Engelman, J. A., Camidge, D. R., Rajan, A., Khuri, F. R., Liang, J. Q., O'Connell, J. P., & Giaccone, G. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.15_suppl.8063 · Cited by 41 · see citing works
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Remarkable Effect of Gefitinib Retreatment in a Patient with Nonsmall Cell Lung Cancer Who Had a Complete Response to Initial Gefitinib
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Efficacy and safety of PF-00299804 (PF299), an oral, irreversible, pan-human epidermal growth factor receptor (pan-HER) tyrosine kinase inhibitor (TKI), as first-line treatment (tx) of selected patients (pts) with advanced (adv) non-small cell lung cancer (NSCLC).
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Current health behaviors and readiness to pursue life-style changes among men and women diagnosed with early stage prostate and breast carcinomas
Demark-Wahnefried, W., Peterson, B., McBride, C., Lipkus, I., & Clipp, E. (2000) · Cancer · doi:10.1002/(sici)1097-0142(20000201)88:3

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Radiomics: Images Are More than Pictures, They Are Data
Gillies, R. J., Kinahan, P. E., & Hricak, H. (2016) · Radiology · doi:10.1148/radiol.2015151169 · Cited by 8,421 · see citing works
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial
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The biology and management of non-small cell lung cancer
Herbst, R. S., Morgensztern, D., & Boshoff, C. (2018) · Nature · doi:10.1038/nature25183 · Cited by 4,891 · see citing works
Cancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681 · see citing works
Tumour heterogeneity and resistance to cancer therapies
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Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer
Mok, T. S., Wu, Y.-L., Ahn, M.-J., Garassino, M. C., Kim, H. R., Ramalingam, S. S., Shepherd, F. A., He, Y., Akamatsu, H., Theelen, W. S. M. E., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1612674 · Cited by 3,379 · see citing works
Lung cancer: current therapies and new targeted treatments
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Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations
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Classification and mutation prediction from non–small cell lung cancer histopathology images using deep learning
Coudray, N., Ocampo, P. S., Sakellaropoulos, T., Narula, N., Snuderl, M., Fenyö, D., Moreira, A. L., Razavian, N., & Tsirigos, A. (2018) · Nature Medicine · doi:10.1038/s41591-018-0177-5 · Cited by 2,930 · see citing works
Influence of tumour micro-environment heterogeneity on therapeutic response
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Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Novello, S., Barlesi, F., Califano, R., Cufer, T., Ekman, S., Levra, M. G., Kerr, K., Popat, S., Reck, M., Senan, S., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw326 · Cited by 2,631 · see citing works
Lung cancer
Thai, A. A., Solomon, B., Sequist, L. V. D., Gainor, J. F., & Heist, R. S. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00312-3 · Cited by 2,629 · see citing works
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EMT, CSCs, and drug resistance: the mechanistic link and clinical implications
Shibue, T., & Weinberg, R. A. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.44 · Cited by 2,539 · see citing works
Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR -Mutant Lung Cancers
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AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer
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Non–Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment
Duma, N., Santana-Dávila, R., & Molina, J. R. (2019) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2019.01.013 · Cited by 2,218 · see citing works
Non-small-cell lung cancers: a heterogeneous set of diseases
Chen, Z., Brainson, C. F., Hammerman, P. S., Kim, C. F., & Wong, K. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3775 · Cited by 1,935 · see citing works
Liquid biopsy: monitoring cancer-genetics in the blood
Crowley, E. H., Nicolantonio, F. D., Loupakis, F., & Bardelli, A. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.110 · Cited by 1,821 · see citing works
Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M
Thress, K. S., Paweletz, C. P., Felip, E., Cho, B. C., Stetson, D., Dougherty, B., Lai, Z., Markovets, A., Vivancos, A., Kuang, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3854 · Cited by 1,589 · see citing works
Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer
Leonetti, A., Sharma, S., Minari, R., Perego, P., Giovannetti, E., & Tiseo, M. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0573-8 · Cited by 1,446 · see citing works
Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer
Peifer, M., Fernandez‐Cuesta, L., Sos, M. L., George, J., Seidel, D., Kasper, L. H., Plenker, D., Leenders, F., Sun, R., Zander, T., et al. (2012) · Nature Genetics · doi:10.1038/ng.2396 · Cited by 1,390 · see citing works
The ErbB/HER family of protein-tyrosine kinases and cancer
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Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers
Katayama, R., Shaw, A. T., Khan, T. M., Mino-Kenudson, M. A., Solomon, B., Halmos, B., Jessop, N. A., Wain, J. C., Yeo, A. T., Benes, C. H., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003316 · Cited by 1,316 · see citing works
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Non–Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology
Ettinger, D. S., Wood, D. E., Aisner, D. L., Akerley, W., Bauman, J. R., Chirieac, L. R., D’Amico, T. A., DeCamp, M. M., Dilling, T. J., Dobelbower, M. C., et al. (2017) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2017.0050 · Cited by 1,305 · see citing works
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Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology
Lindeman, N. I., Cagle, P. T., Beasley, M. B., Chitale, D. A., Dacic, S., Giaccone, G., Jenkins, R. B., Kwiatkowski, D. J., Saldivar, J.-S., Squire, J., et al. (2013) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318290868f · Cited by 1,280 · see citing works
Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data
Rudin, C. M., Poirier, J. T., Byers, L. A., Dive, C., Dowlati, A., George, J., Heymach, J. V., Johnson, J. E. B., Lehman, J. M., MacPherson, D. P., et al. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0133-9 · Cited by 1,251 · see citing works
Acquired Resistance to KRAS G12C Inhibition in Cancer
Awad, M. M., Liu, S., Rybkin, I. I., Arbour, K. C., Dilly, J., Zhu, V. W., Johnson, M. L., Heist, R. S., Patil, T., Riely, G. J., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2105281 · Cited by 1,247 · see citing works
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Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer
Zhang, Z., Lee, J. C., Lin, L., Olivas, V., Au, V., LaFramboise, T., Abdel-Rahman, M., Wang, X., Levine, A. D., Rho, J. K., et al. (2012) · Nature Genetics · doi:10.1038/ng.2330 · Cited by 1,224 · see citing works
Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK -Rearranged Lung Cancer
Gainor, J. F., Dardaei, L., Yoda, S., Friboulet, L., Leshchiner, I., Katayama, R., Dagogo‐Jack, I., Gadgeel, S. M., Schultz, K. R., Singh, M., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0596 · Cited by 1,158 · see citing works
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Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
Wilson, T. R., Fridlyand, J., Yan, Y., Penuel, E., Burton, L., Chan, E., Peng, J., Lin, E., Wang, Y., Sosman, J., et al. (2012) · Nature · doi:10.1038/nature11249 · Cited by 1,134 · see citing works
RAS-targeted therapies: is the undruggable drugged?
Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103 · see citing works
Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance
Ku, S., Rosario, S. R., Wang, Y., Mu, P., Seshadri, M., Goodrich, Z., Goodrich, M. M., Labbé, D. P., Gomez, E. C., Wang, J., et al. (2017) · Science · doi:10.1126/science.aah4199 · Cited by 1,093 · see citing works
Integrated digital error suppression for improved detection of circulating tumor DNA
Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D. M., Chabon, J. J., Scherer, F., Stehr, H., Liu, C. L., Bratman, S. V., Say, C., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3520 · Cited by 1,091 · see citing works
Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non–Small Cell Lung Cancer
Doebele, R. C., Pilling, A. B., Aisner, D. L., Kutateladze, T. G., Le, A. T., Weickhardt, A. J., Kondo, K. L., Linderman, D. J., Heasley, L. E., Franklin, W. A., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2906 · Cited by 1,064 · see citing works
SOX2 promotes lineage plasticity and antiandrogen resistance in TP53 - and RB1 -deficient prostate cancer
Mu, P., Zhang, Z., Benelli, M., Karthaus, W. R., Hoover, E., Chen, C.-C., Wongvipat, J., Ku, S., Gao, D., Cao, Z., et al. (2017) · Science · doi:10.1126/science.aah4307 · Cited by 1,063 · see citing works
ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics
Arteaga, C. L., & Engelman, J. A. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.025 · Cited by 1,048 · see citing works
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The Next-Generation Sequencing Revolution and Its Impact on Genomics
Koboldt, D. C., Steinberg, K. M., Larson, D. E., Wilson, R. K., & Mardis, E. R. (2013) · Cell · doi:10.1016/j.cell.2013.09.006 · Cited by 1,039 · see citing works
Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition
Hata, A. N., Niederst, M. J., Archibald, H. L., Gomez-Caraballo, M., Siddiqui, F. M., Mulvey, H. E., Maruvka, Y. E., Ji, F., Bhang, H.-E. C., Krishnamurthy Radhakrishna, V., et al. (2016) · Nature Medicine · doi:10.1038/nm.4040 · Cited by 985 · see citing works
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Glucocorticoid Receptor Confers Resistance to Antiandrogens by Bypassing Androgen Receptor Blockade
Arora, V. K., Schenkein, E., Murali, R., Subudhi, S. K., Wongvipat, J., Balbas, M., Shah, N., Cai, L., Efstathiou, E., Logothetis, C., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.012 · Cited by 985 · see citing works
Understanding and targeting resistance mechanisms in NSCLC
Rotow, J. K., & Bivona, T. G. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.84 · Cited by 978 · see citing works
The MAPK pathway across different malignancies: A new perspective
Burotto, M., Chiou, V. L., Lee, J., & Kohn, E. C. (2014) · Cancer · doi:10.1002/cncr.28864 · Cited by 960 · see citing works
Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin
Oser, M. G., Niederst, M. J., Sequist, L. V. D., & Engelman, J. A. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(14)71180-5 · Cited by 939 · see citing works
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Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
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Authors: Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., Bergethon, K., Shaw, A. T., Gettinger, S., Cosper, A. K., Akhavanfard, S., Heist, R. S., Temel, J., Christensen, J. G., Wain, J. C., Lynch, T. J., Vernovsky, K., Mark, E. J., Lanuti, M., Iafrate, A. J., Mino-Kenudson, M., & Engelman, J. A.
Affiliations: Harvard University (US)
Massachusetts General Hospital (US)
Yale Cancer Center (US)
Pfizer (United States) (US)
Corresponding author: Sequist, Lecia V.
Waltman, Belinda A.
Dias-Santagata, Dora
Engelman, Jeffrey A.
ORCID: Sequist, Lecia V.
Dias-Santagata, Dora
Digumarthy, Subba
Shaw, Alice T.
Gettinger, Scott
Akhavanfard, Sara
Heist, Rebecca S.
Temel, Jennifer
Christensen, James G.
Wain, John C.
Lynch, Thomas J.
Lanuti, Michael
Iafrate, A. John
Mino-Kenudson, Mari
Engelman, Jeffrey A.
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2011-03-23
Volume: 3
Issue: 75
Pages: 75ra26-75ra26
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.3002003
PMC: PMC3132801
OpenAlex: W1980497534
Cited by: 3,499
References: 64
Citations by year: 2026: 95 · 2025: 141 · 2024: 160 · 2023: 178 · 2022: 249 · 2021: 265 · 2020: 281 · 2019: 259 · 2018: 298 · 2017: 331 · 2016: 279 · 2015: 270 · 2014: 232 · 2013: 253 · 2012: 154
FWCI: 188.37
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Science Translational Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (P50CA127003, U01CA141457, K08 GRANT CA120060-01, R01CA140594, R21CA156000, P50CA090578, P20CA090578, K08CA120060, R01CA137008)
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 inhibitors, drug resistance, non-small cell lung cancer, EGFR mutation, T790M mutation, MET amplification, EGFR amplification, PIK3CA mutation, epithelial-mesenchymal transition, small cell lung cancer transformation, histological evolution, serial biopsies, tyrosine kinase inhibitors
MeSH terms: Erlotinib Hydrochloride, Gefitinib, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Biopsy, Female, Genotype, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Phenotype, Quinazolines, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, ErbB Receptors

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Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors

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