Flavopiridol Synergizes with Sorafenib to Induce Cytotoxicity and Potentiate Antitumorigenic Activity in EGFR/HER-2 and Mutant RAS/RAF Breast Cancer Model Systems

摘要: Oncogenic receptor tyrosine kinase (RTK) signaling through the Ras-Raf-Mek-Erk (Ras-MAPK) pathway is implicated in a wide array of carcinomas, including those breast. The cyclin-dependent kinases (CDKs) are regulating proliferative and survival downstream this pathway. Here, we show that CDK inhibitors exhibit an order magnitude greater cytotoxic potency than suite targeting RTK Ras-MAPK cell lines representative clinically recognized breast cancer (BC) subtypes. Drug combination studies pan-CDK inhibitor, flavopiridol (FPD), synergistically potentiated cytotoxicity induced by Raf sorafenib (SFN). This synergy was most pronounced at sub-EC50 SFN concentrations MDA-MB-231 (KRAS-G13D BRAF-G464V mutations), MDA-MB-468 [epidermal growth factor (EGFR) overexpression], SKBR3 [ErbB2/EGFR2 (HER-2) overexpression] cells but not hormone-dependent MCF-7 T47D cells. Potentiation FPD correlated with enhanced apoptosis, suppression retinoblastoma (Rb) signaling, reduced Mcl-1 expression. were also tested mammary fat pad engraftment model tumorigenesis. Mice treated both drugs exhibited primary tumor rates metastatic load lungs compared to treatment either drug alone, reductions Rb expression resected tumors. These findings support development co-targeting strategies EGFR/HER-2-overexpressing or RAS/RAF mutant BCs.