Cited by 445Lung Cancer Treatments and MutationsMelanoma and MAPK PathwaysHER2/EGFR in Cancer Research

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Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

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Ohashi, Kadoaki, Sequist, Lecia V., Arcila, Maria E., Moran, Teresa, Chmielecki, Juliann, Lin, Ya-Lun, Pan, Yumei, Wang, Lu, de Stanchina, Elisa, Shien, Kazuhiko, Aoe, Keisuke, Toyooka, Shinichi, Kiura, Katsuyuki, Fernandez-Cuesta, Lynnette, Fidias, Panos, Yang, James Chih-Hsin, Miller, Vincent A., Riely, Gregory J., Kris, Mark G., Engelman, Jeffrey A., Vnencak-Jones, Cindy L., Dias-Santagata, Dora, Ladanyi, Marc, Pao, William·2012·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1203530109PMC PMC3411967

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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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10.1371/journal.pmed.0020073 · DOI · Paper page
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10.1242/dmm.003681 · DOI

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Authors: Ohashi, K., Sequist, L. V., Arcila, M. E., Moran, T., Chmielecki, J., Lin, Y.-L., Pan, Y., Wang, L., de Stanchina, E., Shien, K., Aoe, K., Toyooka, S., Kiura, K., Fernandez-Cuesta, L., Fidias, P., Yang, J. C.-H., Miller, V. A., Riely, G. J., Kris, M. G., Engelman, J. A., Vnencak-Jones, C. L., Dias-Santagata, D., Ladanyi, M., & Pao, W.
Affiliations: Vanderbilt University (US)
Harvard University (US)
Department of Pathology,
Catalan Institute of Oncology, Universitat Autonoma de Barcelona and Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Barcelona, Spain;
Cornell University (US)
Anti-Tumor Assessment Core Facility, and
Okayama University Hospital (JP)
National Sanyo Hospital (JP)
Okayama University (JP)
Max Planck Institute for Neurological Research with Klaus Joachim Zülch Laboratories of the Max Planck Society and the Medical Faculty, Cologne 50931, Germany;
National Taiwan University (TW)
Memorial Sloan Kettering Cancer Center (US)
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232; and
ORCID: Ohashi, Kadoaki
Sequist, Lecia V.
Arcila, Maria E.
Chmielecki, Juliann
Wang, Lu
Shien, Kazuhiko
Toyooka, Shinichi
Kiura, Katsuyuki
Yang, James Chih-Hsin
Miller, Vincent A.
Riely, Gregory J.
Kris, Mark G.
Engelman, Jeffrey A.
Dias-Santagata, Dora
Ladanyi, Marc
Pao, William
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2012-07-06
Volume: 109
Issue: 31
Pages: E2127-33
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1203530109
PMC: PMC3411967
OpenAlex: W2096540669
Cited by: 441
References: 42
Citations by year: 2026: 7 · 2025: 13 · 2024: 10 · 2023: 13 · 2022: 16 · 2021: 28 · 2020: 27 · 2019: 23 · 2018: 51 · 2017: 50 · 2016: 54 · 2015: 60 · 2014: 45 · 2013: 40 · 2012: 4
FWCI: 38.40
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Max Planck Institute for Plasma Physics (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Funders: Bristol-Myers Squibb
Pfizer
AstraZeneca
GlaxoSmithKline
Celgene
Clovis Oncology
Agios Pharmaceuticals
Symphogen
U.S. Public Health Service (1R21-156000)
Foundation Medicine
National Cancer Institute (P30 CA 68485, R01CA121210, P01CA129243, CA90949, U54CA143798, P50CA090949, P30CA068485)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords: EGFR tyrosine kinase inhibitors, acquired drug resistance, EGFR-mutant lung cancer, BRAF mutation, NRAS Q61K, KRAS mutation, MEK1 mutations, Ras/Raf/MEK signaling, MEK inhibitor combination, secondary mutations, metastatic lung cancer
MeSH terms: Clinical Trials as Topic, Female, Humans, Lung Neoplasms, Male, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Drug Resistance, Neoplasm, Amino Acid Substitution, Mutation, Missense, Cell Line, Tumor, Protein Kinase Inhibitors, MAP Kinase Kinase 1, Proto-Oncogene Proteins B-raf, ErbB Receptors

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Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

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