The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.
Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
Open accessAbstract
Lung cancers undergo dynamic genetic and histological changes upon developing resistance to EGFR inhibitors.
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“A secondary epidermal growth factor receptor (EGFR) mutation, T790M, is the most common resistance mechanism in EGFR mutant adenocarcinomas that have progressed on erlotinib.”
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“with the EGFR T790M somatic mutation being the most frequent alteration detected in approximately half of progressing tumors.[14][15][16]”
In the citing paper
“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%)”
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Citations
Cites
New Guidelines to Evaluate the Response to Treatment in Solid Tumors
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Self-citationEGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
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“They have identified several resistance mechanisms, two of which—EGFR mutation T790M (6, 7) andMET amplification (8, 9)—have been validated in the clinic.”
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Metadata
- 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
- Venue
- Science Translational Medicine
- Published
- 2011-03-23
- Volume
- 3
- Issue
- 75
- Pages
- 75ra26-75ra26
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- 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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