title: The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF.
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.
authors: Department of Genomic Medicine The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Ian R
authors: IR
authors: Watson
authors: Department of Genomic Medicine The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
authors: Liren
authors: L
authors: Li
authors: Department of Genomic Medicine The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Peter K
authors: PK
authors: Cabeceiras
authors: Department of Genomic Medicine The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Mozhdeh
authors: M
authors: Mahdavi
authors: Department of Genomic Medicine The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Tony
authors: T
authors: Gutschner
authors: Department of Genomic Medicine The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Giannicola
authors: G
authors: Genovese
authors: Department of Cancer Biology The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Guocan
authors: G
authors: Wang
authors: Department of Genomic Medicine The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
authors: Zhuangna
authors: Z
authors: Fang
authors: Department of Genomic Medicine The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: James M
authors: JM
authors: Tepper
authors: Department of Systems Biology The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Katherine
authors: K
authors: Stemke-Hale
authors: Department of Dermatology The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Kenneth Y
authors: KY
authors: Tsai
authors: Department of Systems Biology The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Melanoma Medical Oncology The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Michael A
authors: MA
authors: Davies
authors: Department of Systems Biology The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Gordon B
authors: GB
authors: Mills
authors: Department of Genomic Medicine The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Institute for Applied Cancer Science The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Lynda
authors: L
authors: Chin
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000235:genetics*; D048490:raf Kinases / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C107953:RAC1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D020830:rac1 GTP-Binding Protein