TY - JOUR
T1 - The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF
AU - Watson, Ian R.
AU - Li, Liren
AU - Cabeceiras, Peter K.
AU - Mahdavi, Mozhdeh
AU - Gutschner, Tony
AU - Genovese, Giannicola
AU - Wang, Guocan
AU - Fang, Zhuangna
AU - Tepper, James M.
AU - Stemke-Hale, Katherine
AU - Tsai, Kenneth Y.
AU - Davies, Michael A.
AU - Mills, Gordon B.
AU - Chin, Lynda
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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 BRAFmutant 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.
AB - 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 BRAFmutant 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.
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U2 - 10.1158/0008-5472.CAN-14-1232-T
DO - 10.1158/0008-5472.CAN-14-1232-T
M3 - Article
C2 - 25056119
AN - SCOPUS:84907051443
SN - 0008-5472
VL - 74
SP - 4845
EP - 4852
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -