Dinaciclib, a Bimodal Agent Effective against Endometrial Cancer

SIMPLE SUMMARY: Endometrial cancer (EC) is diagnosed in almost 400,000 women every year globally and is the sixth most common cancer in women. When diagnosed early, treatment can result in a full recovery; however, when at an advanced stage, fewer than 50% of patients survive beyond 5 years and new treatments are needed for these patients. The aim of this investigation was to evaluate cyclin-dependent kinase inhibitors (CDKis) for the treatment of EC using cells isolated directly from patient tumors and cell lines. We compared several CDKis and found one CDKi, dinaciclib, to be particularly toxic to EC cells. Dinaciclib both prevented EC cells from proliferating and blocked transcriptional activity. The drug was equally effective across EC subtypes and combined effectively with cisplatin. This study highlights the potential clinical benefit of dinaciclib for use in the treatment of EC. ABSTRACT: Endometrial cancer (EC) is the sixth most prevalent female cancer globally and although high rates of success are achieved when diagnosed at an early stage, the 5-year survival rate for cancers diagnosed at Stages II–IV is below 50%. Improving patient outcomes will necessitate the introduction of novel therapies to the clinic. Pan-cyclin-dependent kinase inhibitors (CDKis) have been explored as therapies for a range of cancers due to their ability to simultaneously target multiple key cellular processes, such as cell cycle progression, transcription, and DNA repair. Few studies, however, have reported on their potential for the treatment of EC. Herein, we examined the effects of the pan-CDKi dinaciclib in primary cells isolated directly from tumors and EC cell lines. Dinaciclib was shown to elicit a bimodal action in EC cell lines, disrupting both cell cycle progression and phosphorylation of the RNA polymerase carboxy terminal domain, with a concomitant reduction in Bcl-2 expression. Furthermore, the therapeutic potential of combining dinaciclib and cisplatin was explored, with the drugs demonstrating synergy at specific doses in Type I and Type II EC cell lines. Together, these results highlight the potential of dinaciclib for use as an effective EC therapy.