ArticleProceedings of the National Academy of Sciences of the United States of America2012
Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 252 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
252 citing papers in PubMed, 2 syntheses or guidelines pooled it, 435 citations in OpenAlex.
- RRM1 expression is associated with the outcome of gemcitabine-based treatment of non-small cell lung cancer patients--a short report.Cellular oncology (Dordrecht, Netherlands) · 2015Pooled it
- Transcriptional changes associated with resistance to inhibitors of epidermal growth factor receptor revealed using metaanalysis.BMC cancer · 2015Pooled it
- Phase I/II Study of Erlotinib to Determine the Optimal Dose in Patients With Non-Small Cell Lung Cancer Harboring Only EGFR Mutations.Clinical and translational science · 2020Trial
- A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2017Trial
- A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor (Cancer research and treatment · 2017Trial
- Trial
- Phase I/II Study of HSP90 Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2015Trial
- Fc-Dependent Targeting of the GAS6-MERTK Axis With Monoclonal and Bispecific Antibodies Overcomes Drug Resistance Across EGFR Mutations in Exons 19, 20, and 21.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Variant-Specific Landscape of Mutual Exclusivity Among BRAF, EGFR, and KRAS Oncogenes Reveals Overlap With Functionally Antagonistic Mutant Pairs.International journal of cancer · 2026Article
- Opportunities and challenges in the development of evolving EGFR inhibitors to overcome EGFR TKIs resistance.Acta pharmacologica Sinica · 2026Review
- Uncovering functional variants using a high-efficiency PE3-based screening platform.Science advances · 2026Article
- A genome-wide genetic screen reveals the P2Y2-integrin axis as a stabilizer of EGFR mutants in non-small cell lung cancer (NSCLC).Science advances · 2026Article
- Cytoskeletal remodeling via CAMSAP3 downregulation drives resistance to osimertinib in NSCLC cells.Cell death & disease · 2025Article
- Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Common Mutations: New Strategies.Cancers · 2025Review
- Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics.Cancers · 2025Review
- Exosome, an important transmitter in the drug resistance of non-small cell lung cancer.Frontiers in oncology · 2025Review
- Genetic heterogeneity and key driver mutations in the preneoplastic and earliest stages of gastric cancer.Gastroenterology report · 2025Article
- Expert consensus on the diagnosis and treatment of solid tumors with BRAF mutations.Innovation (Cambridge (Mass.)) · 2024Review
- Triple-targeted therapy of dabrafenib, trametinib, and osimertinib for the treatment of the acquiredTranslational lung cancer research · 2024Article
- Design, synthesis, and biological evaluation of novel quinoline-based EGFR/HER-2 dual-target inhibitors as potential anti-tumor agents.RSC advances · 2024Article
192 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 14 institutions in 6 countries.
Funding
Abstract
Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.