| Two-thirds of the annual newly diagnosed cases of ovarian cancer fall under the category of high-grade serous ovarian cancer, a deadly malignancy that has shown no improvement in mortality rates in the past 40 years. A ray of hope for ovarian cancer patients has been the discovery of PARP poly [ADP-ribose] polymerase inhibitors, which have activity against cancers with defects in Homologous Recombination (HR), a DNA repair process that requires BRCA1 and BRCA2. Accordingly, tumors with mutations in BRCA1 and BRCA2, which account for 15-20% of these cancers, often respond to PARP inhibitors. However, it is likely that many other ovarian tumors without BRCA1 and BRCA2 mutations will also respond to PARP inhibitors because upwards of 50% of ovarian tumors have defects in HR; however, the genetic defects that disrupt HR in these tumors are not well defined. To identify other gene mutations that disrupt HR in ovarian cancer, we focused on CDK12 (Cyclin Dependent Kinase -- 12) which was recently shown to be somatically mutated in high-grade serous ovarian cancer and to regulate BRCA1 levels. We investigated the effect of the ovarian cancer-associated mutations on the enzymatic activity of CDK12 and whether CDK12 activity was important in ovarian cancer cells to carry out HR. We found that these CDK12 mutations disrupted its enzymatic activity and disabled HR in ovarian cancer cells. We also found that HR can be restored in CDK12-depleted ovarian cancer cells by the wild-type but not by the ovarian cancer-associated mutant form of CDK12. Additionally, we noted that ovarian cancer cells with dysfunctional CDK12 are susceptible to PARP inhibitors (ABT-888) and chemotherapy drugs that induce damage repaired by HR (melphalan and cisplatin). Our results showing that CDK12 is important for HR and that mutations in CDK12 cause defective HR suggest that CDK12 mutation may be a biomarker to identify ovarian cancer patients who might benefit from PARP inhibitor treatment. Even though we know that CDK12 is important for HR, the exact mechanism of its action is unknown. Current efforts are directed at determining the mechanisms by which CDK12 regulates HR. The preliminary data indicate that CDK12 regulates the splicing of genes important for HR by interacting with the spliceosome associated proteins CDC5L and PRP19. Studies are underway to map these interactions and understand their significance in ovarian cancer. |
