1. The RAC1 P29S Hotspot Mutation in Melanoma Confers Resistance to Pharmacological Inhibition of RAF
- Author
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Tony Gutschner, Peter K. Cabeceiras, Kenneth Y. Tsai, James Tepper, Giannicola Genovese, Michael A. Davies, Liren Li, Zhuangna Fang, Ian R. Watson, Katherine Stemke-Hale, Gordon B. Mills, Guocan Wang, Lynda Chin, and Mozhdeh Mahdavi
- Subjects
Proto-Oncogene Proteins B-raf ,rac1 GTP-Binding Protein ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,Apoptosis ,RAC1 ,Biology ,Article ,Germline mutation ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Humans ,Gene silencing ,Vemurafenib ,Melanoma ,Protein Kinase Inhibitors ,neoplasms ,Cancer ,Dabrafenib ,medicine.disease ,Oncology ,Drug Resistance, Neoplasm ,Mutation ,Cancer research ,raf Kinases ,medicine.drug - Abstract
Following mutations in BRAF and NRAS, the RAC1 c.85C>T single-nucleotide variant (SNV) encoding P29S amino acid change represents the next most frequently observed protein-coding hotspot mutation in melanoma. However, the biologic and clinical significance of the RAC1 P29S somatic mutation in approximately 4% to 9% of patients remains unclear. Here, we demonstrate that melanoma cell lines possessing the RAC1 hotspot variant are resistant to RAF inhibitors (vemurafenib and dabrafenib). Enforced expression of RAC1 P29S in sensitive BRAF-mutant melanoma cell lines confers resistance manifested by increased viability, decreased apoptosis, and enhanced tumor growth in vivo upon treatment with RAF inhibitors. Conversely, RNAi-mediated silencing of endogenous RAC1 P29S in a melanoma cell line with a co-occurring BRAF V600 mutation increased sensitivity to vemurafenib and dabrafenib. Our results suggest RAC1 P29S status may offer a predictive biomarker for RAF inhibitor resistance in melanoma patients, where it should be evaluated clinically. Cancer Res; 74(17); 4845–52. ©2014 AACR.
- Published
- 2014
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