Inhibition of cyclin-dependent kinases by AT7519 is effective to overcome chemoresistance in colon and cervical cancer

Abstract

Cyclin-dependent kinases (CDK), a family of heterodimeric kinases that play central roles in regulation of cell cycle progression and transcription, have garnered attention in recent years because their aberrant activity has been reported in a wide variety of human cancers. AT7519 is a multitargeted CDK inhibitor that is currently in clinical trials for the treatment of refractory blood cancers. In this work, we are the first to provide preclinical evidence that AT7519 is an attractive candidate to overcome chemoresistance in colon and cervical cancer. We show that AT7519 is effective in targeting a panel of colon and cervical cancer cell lines, with IC50 range from 0.1 to 1 μM. Importantly, AT7519 at similar IC50 range inhibits growth and induces apoptosis of paclitaxel-resistant cervical cancer cells and 5-FU-resistant colon cancer cells. AT7519 at sublethal concentration remarkably augments the inhibitory effects of 5-FU and paclitaxel in colon and cervical cancer cells. Mechanistically, we show that AT7519 suppresses phosphorylation of CDK1, CDK2 and RNA polymerase II in chemoresistant colon and cervical cancer cells. We further confirm the efficacy of AT7519 and its mechanisms of the action using two independent chemoresistant xenograft mouse models: 5-FU-resistant colony cancer xenograft and paclitaxel-resistant cervical cancer xenograft. Our findings support the clinical trials of AT7519 for cancer treatment. Our work also demonstrates the therapeutic value of inhibiting CDK in chemoresistant cancers.