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

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

doi:10.1073/pnas.1203530109

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

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 +16 more·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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Re-activation of ERK signaling can promote resistance to EGFR inhibitors as evidenced by the finding of a BRAF mutation in an EGFR mutant lung cancer with acquired resistance.
“In addition to reactivation of PI3K, re-activation of ERK signaling can promote resistance to EGFR inhibitors as evidenced by the finding of a BRAF mutation in an EGFR mutant lung cancer with acquired resistance (Ohashi et al., 2012).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Ohashi et al., 2012

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Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence
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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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Resisting Resistance: Targeted Therapies in Lung Cancer
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“An extensive study examined potential involvement of mutations in BRAF, NRAS, KRAS, and MEK1 in a large number of resistant tumors, and found no evidence of secondary mutations in these genes with the exception of BRAF, where mutations were identified in 2 of 195 (1%) biopsies [48].”
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SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer
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EGFR-Targeted Therapy for Non-Small Cell Lung Cancer: Focus on EGFR Oncogenic Mutation
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Resistance to ROS1 Inhibition Mediated by EGFR Pathway Activation in Non-Small Cell Lung Cancer
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Pattern of Failure Analysis in Metastatic EGFR-Mutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy
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Lessons Learned From Lung Cancer Genomics: The Emerging Concept of Individualized Diagnostics and Treatment
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EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer
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Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer
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Gli1-Mediated Regulation of Sox2 Facilitates Self-Renewal of Stem-Like Cells and Confers Resistance to EGFR Inhibitors in Non–Small Cell Lung Cancer
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Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer
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YAP-Dependent AXL Overexpression Mediates Resistance to EGFR Inhibitors in NSCLC
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Molecular Signatures of the Insulin-Like Growth Factor 1-Mediated Epithelial-Mesenchymal Transition in Breast, Lung and Gastric Cancers
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Current knowledge of small cell lung cancer transformation from non-small cell lung cancer
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Role of artificial intelligence in the care of patients with nonsmall cell lung cancer
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Expanding the Multiplexing Capabilities of Raman Imaging to Reveal Highly Specific Molecular Expression and Enable Spatial Profiling
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Abstract 1897: RAS signaling pathway gene mutations and acquired resistance to EGFR tyrosine-kinase inhibitors in EGFR mutant lung cancer
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Acquired BRAF Rearrangements Induce Secondary Resistance to EGFR therapy in EGFR-Mutated Lung Cancers
Vojnic, M., Kubota, D., Kurzatkowski, C., Offin, M. D., Suzawa, K., Benayed, R., Schoenfeld, A. J., Plodkowski, A. J., Poirier, J. T., Rudin, C. M., et al. (2019) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.12.038 · Cited by 104 · see citing works
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Acquired BRAF fusions as a mechanism of resistance to EGFR therapy.
Vojnic, M., Kurzatkowski, C., Kubota, D., Suzawa, K., Liu, Z., Mattar, M. S., Khodos, I., Poirier, J. T., de Stanchina, E., Rudin, C. M., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2018.36.15_suppl.12122 · Cited by 2 · see citing works
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P2.09-14 Clinical Characteristics and Outcomes of Patients with EGFR-mutant Lung Cancer with Acquired BRAF Alterations
Sui, J. S. Y., Yang, S., Bowman, A. S., Vankayala, P., Falcon, C. J., Somwar, R., Drilon, A. E. D. C., Riely, G. J., Kris, M. G., Ladanyi, M., et al. (2023) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2023.09.588 · Cited by 1 · see citing works
Self-citation
In This Issue/Research Watch/News-in-Brief/News from the IASLC Tobacco Control Committee
(2019) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2019.03.012

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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