Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
109
Journal Issue
31
Pages
E2127-E2133
Date Issued
2012
Author(s)
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
Miller V.A
Riely G.J
Kris M.G
Engelman J.A
Vnencak-Jones C.L
Dias-Santagata D
Ladanyi M
Pao W.
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.
Subjects
Erlotinib; Gefitinib; Nras mutation
SDGs
Other Subjects
B Raf kinase; epidermal growth factor receptor kinase inhibitor; erlotinib; guanosine triphosphatase; K ras protein; mitogen activated protein kinase kinase 1; selumetinib; article; cancer cell; cancer cell culture; colon cancer; digestive system cancer; disease course; gene expression; gene mutation; human; human cell; IC 50; in vitro study; lung cancer; melanoma; priority journal; Amino Acid Substitution; Cell Line, Tumor; Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; MAP Kinase Kinase 1; Mutation, Missense; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; ras Proteins; Receptor, Epidermal Growth Factor
Type
journal article