CRIF1-CDK2 Interface Inhibitors Enhance Taxol Inhibition of the Lethal Triple-Negative Breast Cancer.

Abstract

Simple SummaryThis study reported our most recent results for targeting triple-negative breast cancer (TNBC) with a low survival rate, using CR6-interacting factor 1–cyclin-dependent kinase 2 (CRIF1–CDK2) interface inhibitors, by inhibiting the resistance to taxol treatment. Presently, over 50% of TNBC patients become resistant to chemotherapy and, to date, no solution is available. The combined treatment, using CRIF1–CDK2 interface inhibitors with chemotherapy, provides an unprecedented strategy against the deadly TNBC.Paclitaxel (taxol), a chemotherapeutic agent, remains the standard of care for the lethal triple-negative breast cancer (TNBC). However, over 50% of TNBC patients become resistant to chemotherapy and, to date, no solution is available. CR6-interacting factor 1 (CRIF1) is reported to act as a negative regulator of the cell cycle by interacting with cyclin-dependent kinase 2 (CDK2). In our study, two selective CRIF1–CDK2 interface inhibitors were used to investigate whether they could exert anti-proliferative activity on the TNBC cell lines. When combined with taxol treatment, these two inhibitors can advance the cells from G0/G1 to S and G2/M phases, producing irreparable damage to the cells, which then undergo apoptosis. Moreover, they enhanced the reduction in cell proliferation induced by taxol in TNBC cells, thereby improving sensitivity to taxol in these cell lines. Importantly, the inhibitors did not regulate the cell cycle in normal cells, indicating their high selectivity towards TNBC cells. Overall, the resistance to the anti-proliferative effects induced by taxol can be significantly reduced by the combined treatment with selective CRIF1–CDK2 interface inhibitors, making a conceptual advance in the CDK-related cancer treatment.