BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation
- 23 November 2010
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 3 (149), ra84
- https://doi.org/10.1126/scisignal.2001148
Abstract
Oncogenic BRAF mutations are found in several tumor types, including melanomas and colorectal cancers. Tumors with BRAF mutations have increased mitogen-activated protein kinase pathway activity and heightened sensitivity to BRAF and MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase) inhibitors. To identify potential mechanisms of acquired drug resistance, we generated clones resistant to the allosteric MEK inhibitor AZD6244 from two BRAF V600E mutant colorectal cancer cell lines that are highly sensitive to MEK or BRAF inhibition. These AZD6244-resistant (AR) clones, which exhibited cross-resistance to BRAF inhibitors, acquired resistance through amplification of the BRAF gene. A small percentage of treatment-naïve parental cells showed preexisting BRAF amplification. We observed similar amplification in a subset of cells in a BRAF-mutant colorectal cancer. In cell lines, BRAF amplification increased the abundance of phosphorylated MEK and impaired the ability of AZD6244 to inhibit ERK (extracellular signal–regulated kinase) phosphorylation. The ability of AZD6244 to inhibit ERK phosphorylation in AR cells was restored by treatment with a BRAF inhibitor at low concentrations that reduced the abundance of phosphorylated MEK to amounts observed in parental cells. Combined MEK and BRAF inhibition fully overcame resistance to MEK or BRAF inhibitors alone and was also more effective in parental cells compared to treatment with either inhibitor alone. These findings implicate BRAF amplification as a mechanism of resistance to both MEK and BRAF inhibitors and suggest combined MEK and BRAF inhibition as a clinical strategy to overcome, or possibly prevent, this mechanism of resistance.Keywords
This publication has 29 references indexed in Scilit:
- Inhibition of Mutated, Activated BRAF in Metastatic MelanomaThe New England Journal of Medicine, 2010
- Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLCCancer Cell, 2010
- MEK1 mutations confer resistance to MEK and B-RAF inhibitionProceedings of the National Academy of Sciences of the United States of America, 2009
- Colorectal cancer cells with the BRAFV600E mutation are addicted to the ERK1/2 pathway for growth factor-independent survival and repression of BIMOncogene, 2008
- Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for neuroblastoma differentiationProceedings of the National Academy of Sciences of the United States of America, 2008
- Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profilingProceedings of the National Academy of Sciences of the United States of America, 2007
- MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 SignalingScience, 2007
- BRAF mutation predicts sensitivity to MEK inhibitionNature, 2005
- Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibitionNature Structural & Molecular Biology, 2004
- Mutations of the BRAF gene in human cancerNature, 2002