Inhibition of cyclin-dependent kinases by AT7519 enhances nasopharyngeal carcinoma cell response to chemotherapy.

Abstract

The poor outcomes in nasopharyngeal carcinoma (NPC) necessitate new treatments. AT7519 is a potent inhibitor of several cyclin-dependent kinases (CDKs) and is currently in the early phase of clinical development for cancer treatment. The potent anti-cancer activities of AT7519 have been reported in various cancers, but not in NPC. The effects of AT7519 in NPC were systematically analyzed using cell culture assays and xenograft mouse models. The effects of AT7519 on molecules involved in mRNA transcription were examined. AT7519, at a nanomolar concentration, significantly inhibits growth via arresting cells at G2/M phase, and induces apoptosis in NPC cells regardless of Epstein-Barr virus (EBV) infection and cellular origin. It also inhibits growth of a subpopulation of cells with highly proliferative and invasive features. Importantly, AT7519 acts synergistically with cisplatin and is effective against chemo-resistant NPC cells. Mechanistically, AT7519 inhibits phosphorylation of Rb, suggesting the inhibition of CDK2 in NPC. It also decreases N-myc level and RNA polymerase II phosphorylation, and inhibits transcription. Consistent with the in vitro findings, we demonstrate that AT7519 is effective asa single agent in two independent NPC xenograft mouse models. The combination of ATP7519 and cisplatin results in greater efficacy than cisplatinalone in inhibiting NPC tumor growth. Our work is the first to report anti-NPC activities of AT7519. Our preclinical evidence suggests that AT7519 is a useful addition to overcome NPC chemo-resistance.