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

   

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.
Article 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.
Keywords:	gene mutation; human cell; mutation, missense; proto-oncogene proteins; disease course; erlotinib; clinical trials as topic; melanoma; gene expression; mitogen activated protein kinase kinase 1; amino acid substitution; lung neoplasms; lung cancer; receptor, epidermal growth factor; cancer cell culture; in vitro study; drug resistance, neoplasm; cell line, tumor; digestive system cancer; protein kinase inhibitors; colon cancer; cancer cell; gefitinib; ras proteins; ic 50; k ras protein; b raf kinase; map kinase kinase 1; proto-oncogene proteins b-raf; epidermal growth factor receptor kinase inhibitor; guanosine triphosphatase; selumetinib; nras mutation
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	109
Issue:	31
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2012-07-31
Start Page:	E2127
End Page:	E2133
Language:	English
DOI:	10.1073/pnas.1203530109
PROVIDER:	scopus
PMCID:	PMC3411967
PUBMED:	22773810
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84864524696&partnerID=40&md5=5e1d52b4b8e3843516e4481e07b5da8d
Notes:	--- - "Export Date: 4 September 2012" - "CODEN: PNASA" - "Source: Scopus"