CDK2 Inhibition and Eradication of Aneuploid Cancers: Promise Meets Resistance.

Aneuploidy is a cancer hallmark that causes resistance to anticancer drugs and promotes aggressive tumors. Thus, aneuploidy is a consequential feature of human malignancy. This review addresses how cyclin-dependent kinase 2 (CDK2) inhibition targets a broad array of aneuploid cancers for proapoptotic death by engaging a death program called anaphase catastrophe. This program eliminates aneuploid cancers while sparing non-aneuploid epithelial cells, thereby providing a favorable therapeutic window. Despite CDK2 inhibition, a residual population of polyploid cancer cells persists in both in vitro and in vivo settings. This polyploid cancer cell population is resistant to apoptosis conferred by CDK2 inhibition of aneuploid cancers. This provides a basis for clinical drug resistance. The triggering apoptotic death of aneuploid cancers via CDK2 antagonism is compromised by the presence of this apoptosis-resistant population. To elucidate the nature of this polyploid population, these apoptotic-resistant cells were isolated and were found enriched for expressed cyclin-dependent kinase 1 (CDK1) and kinesin superfamily proteins (KIFs). Intriguingly, combining CDK2 inhibition with antagonists for CDK1 or KIF species markedly promoted anticancer effects in aneuploid cancers. This clinically-tractable combined regimen is hypothesized to expose aneuploid cancers to eradication after CDK2 antagonism. Future clinical trials should explore this possibility.