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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 31; pp. E2127 - E2133
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 31.07.2012; National Acad Sciences
• Series: PNAS Plus
• Subjects: Amino Acid Substitution; Biological Sciences; Cell Line, Tumor; Cells; clinical trials; Clinical Trials as Topic; colorectal neoplasms; Drug Resistance, Neoplasm; epidermal growth factor receptors; Female; gastrointestinal system; Gene expression; genes; Humans; Kinases; Lung cancer; lung neoplasms; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Male; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; melanoma; Metastasis; mutants; Mutation; Mutation, Missense; neoplasm cells; patients; PNAS Plus; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; ras Proteins - metabolism; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Tumors; tyrosine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1203530109

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.