PMID- 22773810 OWN - NLM STAT- MEDLINE DCOM- 20121026 LR - 20220409 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 109 IP - 31 DP - 2012 Jul 31 TI - Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. PG - E2127-33 LID - 10.1073/pnas.1203530109 [doi] AB - 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. FAU - Ohashi, Kadoaki AU - Ohashi K AD - Division of Hematology-Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. FAU - Sequist, Lecia V AU - Sequist LV FAU - Arcila, Maria E AU - Arcila ME FAU - Moran, Teresa AU - Moran T FAU - Chmielecki, Juliann AU - Chmielecki J FAU - Lin, Ya-Lun AU - Lin YL FAU - Pan, Yumei AU - Pan Y FAU - Wang, Lu AU - Wang L FAU - de Stanchina, Elisa AU - de Stanchina E FAU - Shien, Kazuhiko AU - Shien K FAU - Aoe, Keisuke AU - Aoe K FAU - Toyooka, Shinichi AU - Toyooka S FAU - Kiura, Katsuyuki AU - Kiura K FAU - Fernandez-Cuesta, Lynnette AU - Fernandez-Cuesta L FAU - Fidias, Panos AU - Fidias P FAU - Yang, James Chih-Hsin AU - Yang JC FAU - Miller, Vincent A AU - Miller VA FAU - Riely, Gregory J AU - Riely GJ FAU - Kris, Mark G AU - Kris MG FAU - Engelman, Jeffrey A AU - Engelman JA FAU - Vnencak-Jones, Cindy L AU - Vnencak-Jones CL FAU - Dias-Santagata, Dora AU - Dias-Santagata D FAU - Ladanyi, Marc AU - Ladanyi M FAU - Pao, William AU - Pao W LA - eng GR - U54 CA143798/CA/NCI NIH HHS/United States GR - P30-CA68485/CA/NCI NIH HHS/United States GR - R01 CA121210/CA/NCI NIH HHS/United States GR - P30 CA068485/CA/NCI NIH HHS/United States GR - U54-CA143798/CA/NCI NIH HHS/United States GR - R01-CA121210/CA/NCI NIH HHS/United States GR - CA90949/CA/NCI NIH HHS/United States GR - 1R21-156000/PHS HHS/United States GR - P50 CA090949/CA/NCI NIH HHS/United States GR - P01-CA129243/CA/NCI NIH HHS/United States GR - P01 CA129243/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120706 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (KRAS protein, human) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Proto-Oncogene Proteins) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.1 (BRAF protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - EC 2.7.12.2 (MAP2K1 protein, human) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Amino Acid Substitution MH - Cell Line, Tumor MH - Clinical Trials as Topic MH - *Drug Resistance, Neoplasm MH - ErbB Receptors/*antagonists & inhibitors/genetics/*metabolism MH - Female MH - Humans MH - Lung Neoplasms/drug therapy/*enzymology MH - MAP Kinase Kinase 1/genetics/*metabolism MH - Male MH - *Mutation, Missense MH - Protein Kinase Inhibitors/*pharmacology/therapeutic use MH - Proto-Oncogene Proteins/genetics/*metabolism MH - Proto-Oncogene Proteins B-raf/genetics/*metabolism MH - Proto-Oncogene Proteins p21(ras) MH - ras Proteins/genetics/*metabolism PMC - PMC3411967 COIS- Conflict of interest statement: L.V.S. received consulting fees from Clovis Oncology, GlaxoSmithKline, and Celgene Corporation. J.C.-H.Y. received consulting fees from Boehringer Ingelheim. V.A.M. is an employee at Foundation Medicine and has equity value in the company. M.G.K. has received consulting fees from Boehringer Ingelheim and research funding for other projects from Pfizer and Boehringer. J.A.E. has received consulting fees and has stock option ownership in Agios Pharmaceuticals and has received research funding for other projects from Novartis, GlaxoSmithKline, and AstraZeneca. D.D.-S. received consulting fees from Bio-Reference Laboratories. W.P. has received consulting fees from MolecularMD, AstraZeneca, Bristol-Myers Squibb, Symphony Evolution, and Clovis Oncology and research funding for other projects from Enzon, Xcovery, AstraZeneca, and Symphogen. W.P. and V.A.M. are part of a patent regarding EGFR T790M mutation testing that was licensed by Memorial Sloan-Kettering Cancer Center to MolecularMD. EDAT- 2012/07/10 06:00 MHDA- 2012/10/27 06:00 PMCR- 2012/07/06 CRDT- 2012/07/10 06:00 PHST- 2012/07/10 06:00 [entrez] PHST- 2012/07/10 06:00 [pubmed] PHST- 2012/10/27 06:00 [medline] PHST- 2012/07/06 00:00 [pmc-release] AID - 1203530109 [pii] AID - 201203530 [pii] AID - 10.1073/pnas.1203530109 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):E2127-33. doi: 10.1073/pnas.1203530109. Epub 2012 Jul 6.