The cytotoxic and apoptotic effects of Palbocyclib-Vemurafenib combination in BRAF and CDKN2A mutant human A375 melanoma cells

In the recent years, despite of improvements in outcome and survival at melanoma patients mainly due to new systemic treatment strategies with targeted therapy, melanoma is still a non-curative and fatal cancer. Although BRAF inhibitors, such as Vemurafenib, are effective on BRAF mutant melanomas, developing resistance limits the efficency of drug in long-term period. Combination strategies did not improve progression free and overall survival, sufficiently. CDK 4/6 (cyclin dependent kinase)-cyclin D-Rb (retinoblastoma) pathway controls cell cycle progression and the presence of mutations on this pathway in melanoma results to become therapeutic target. In this study, we observed cytotoxic and apoptotic effects of Palbosiklib and Vemurafenib as a single agent and combination. After treating A375 cell line, homozygous BRAF and CDKN2A mutant, with Palbocyclib and Vemurafenib during 48 hours, cytotoxic effects of drug were tested. The cytotoxic effects of Palbosiklib are, respectively, %7 in 5 ϻM concentration, %15 in 10 ϻM, %40 in 25 ϻM, %77 in 50 ϻM, %88 in 75 ϻM and %93 in 100 ϻM. The cytotoxic effects of Vemurafenib are, respectively, %34.5 in 5 ϻM concentration, %50 in 10 ϻM, %63.8 in 25 ϻM, %67 in 50 ϻM, %73 in 75 ϻM, %82.5 in 100 ϻM. It was shown that concurrent applications of drugs are more cytotoxic than single agents and also this effect is sinergistic. IC50 value for Palbosiklib is 25.2 ϻM, for Vemurafenib is 12.23 ϻM. In high drug concentrations which are close to IC50 value, apoptosis is triggered with both single agent treatment and concurrent treatment. It is not seem any apoptotic effect with low concentrations of drugs. In this study, for the first time, it was shown that Palbocyclib is a cytotoxic agent on BRAF mutant melanoma cell lines as a single agent or combination therapy with Vemurafenib and synergistic effect might play a role in combination therapy, moreover this cytotoxic effect may be related with apoptosis. In conclusion, these results support single agent Palbocyclib and Palbocyclib/Vemurafenib combination may be novel therapeutic treatment strategies for BRAF mutant melanoma patients in future.