Castration-resistant prostate cancer cells are addicted to the high activity of cyclin-dependent kinase 2.

Cyclin-dependent kinases (CDK) drive the progression through the cell cycle and thereby form classical targets for cancer therapy. Targeting androgen receptor (AR) is effective against prostate cancer (PC), but frequently leads to development of incurable castration-resistant PC (CRPC). We show that emergence of CRPC is associated with significant upregulation of CDK2 cyclins and downregulation of CDK4/6 cyclins. This rewiring renders CRPC cells dependent on the high CDK2 activity, and CDK2-specific inhibitors efficiently decrease proliferation of PC and CRPC cells. We develop a CDK2 inhibitor-resistant CRPC model and perform a rational compound screen to assess which of the currently used anti-CRPC treatments could augment CDK2 therapy-response. This dual approach revealed that when our CRPC model acquired resistance to CDK2 inhibition, it increased AR signaling, and the combination of CDK2 inhibition with anti-androgens induces synergistic antiproliferative effects on CRPC cells. Importantly, CDK2 inhibitors also show synergistic interaction with cell cycle poisons such as Docetaxel and Cisplatin, and combinatorial effects are also seen with radiotherapy, thereby offering multiple combinations against CRPC. In brief, we propose that CDK2 inhibition provides a rational basis for combinatorial therapy against CRPC.