Targeting chemoresistant ovarian malignancies to cytostatic drugs and PARPinhibitors by inhibition of CDK12 kinase activity

Introduction

Ovarian cancer ranks fifth in cancer deaths among women in the USA. Despite tremendous advances in therapy, initial response to therapy is around 70%, tumor recurrences still occur in the majority of ovarian cancer patients converging to chemoresistant disease. Therefore, it is critical to identify and understand molecular mechanisms and biological pathways orchestrating such a resistance. As a result of such a need, new therapy aimed to inhibit activity of poly (ADP-ribose) polymerase (PARP) or checkpoint kinase 1 (Chk1) has emerged, and specific PARP and Chk1 inhibitors are currently being tested in clinical trials. Recently, we have identified cyclin-dependent kinase 12 (CDK12) as a critical cellular factor corrupting DNA-damage repair (DDR) pathway due to aberrant expression of key DDR genes, such as BRCA1, ATM, ATR, FANCI, FANCD2. Most importantly, two groups independently identified that CDK12 silencing in several ovarian cell lines and two HGSOC models caused sensitivity to PARP inhibitors and the replication fork stalling agent cisplatin. Therefore, we were testing if silencing of CDK12 will lead to sensitization to Chk1 inhibitors as well.

Materials/methods

At the moment, we are generating ovarian cell lines with potential to chemically inhibit CDK12 activity by synthetic ATP-analog in order to test if targeting CDK12 will sensitize given cell lines to cytostatic drugs and PARP inhibitors.

Results and conclusions

We believe that identification of small molecules affecting DDR pathways is a promising strategy to overcome cisplatin and PARP resistance. Since CDK12 seems to be indispensable for proper DDR pathway, we propose to incorporate inhibition of CKD12 by small chemical inhibitors as a promising strategy to overcome PARP, Chk1 and cisplatin chemoresistance in patients.