Concurrent targeting of BMI1 and CDK4/6 inhibited breast cancer tumorigenicity in vitro and in vivo

Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge. Intratumoral heterogeneity appears to play crucial role in drug resistance; therefore, combination-based approaches are currently gaining momentum. In the current study, we investigated the ramifications of concurrent targeting of tumor-initiating cells (using BMI1 specific inhibitor, PTC-209) and cell cycle progressiontargeting CDK4/CDK6 using palbociclib on breast, colorectal and prostate cancer cell growth in vitro and in vivo. PTC-209 reduced BMI1 protein expression, while palbociclib (PB) inhibitedCDK4, Rb, and PRb Ser795 phosphorylation. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231, HCT-116, and PC-3 cell models, which was more profound in the combination group. Global gene expression profiling in MDA-MB-231 treated with PTC-209 revealed multiple affected cellular pathways including insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency. On the other hand, PB treatment ofMDA-MB-231 led to substantial changes in gene expression affecting mainly cell cycle progression. PTC-209 and palbociclib reduced colony formation potential, sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Consistent with our results in vitro, combination treatment of PTC-209 and palbociclib reduced tumor growth more profoundly than either of these drugs alone in in vivo model of MDA-MD-231 cells. Therefore, our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colorectal, and prostate cancer.