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

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...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2012-07, Vol.109 (31), p.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: Article
Language:English
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
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1203530109