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

Abstract

Background: 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.

Materials and methods: 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.

Results: 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 as a single agent in two independent NPC xenograft mouse models. The combination of ATP7519 and cisplatin results in greater efficacy than cisplatin alone in inhibiting NPC tumor growth.

Conclusions: 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.

Keywords: AT7519; CDK inhibitor; Chemo-resistance; NPC; Transcription.