title: Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.
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.
authors: Division of Hematology-Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Kadoaki
authors: K
authors: Ohashi
authors: Lecia V
authors: LV
authors: Sequist
authors: Maria E
authors: ME
authors: Arcila
authors: Teresa
authors: T
authors: Moran
authors: Juliann
authors: J
authors: Chmielecki
authors: Ya-Lun
authors: YL
authors: Lin
authors: Yumei
authors: Y
authors: Pan
authors: Lu
authors: L
authors: Wang
authors: Elisa
authors: E
authors: de Stanchina
authors: Kazuhiko
authors: K
authors: Shien
authors: Keisuke
authors: K
authors: Aoe
authors: Shinichi
authors: S
authors: Toyooka
authors: Katsuyuki
authors: K
authors: Kiura
authors: Lynnette
authors: L
authors: Fernandez-Cuesta
authors: Panos
authors: P
authors: Fidias
authors: James Chih-Hsin
authors: JC
authors: Yang
authors: Vincent A
authors: VA
authors: Miller
authors: Gregory J
authors: GJ
authors: Riely
authors: Mark G
authors: MG
authors: Kris
authors: Jeffrey A
authors: JA
authors: Engelman
authors: Cindy L
authors: CL
authors: Vnencak-Jones
authors: Dora
authors: D
authors: Dias-Santagata
authors: Marc
authors: M
authors: Ladanyi
authors: William
authors: W
authors: Pao
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins