Dual targeting of Aurora Kinase A and poly (ADP-ribose) polymerase as a therapeutic option for patients with ovarian cancer: preclinical evaluations.

Abstract

Purpose: Epithelial ovarian cancers (EOCs) are often diagnosed at an advanced stage, leading to poor survival outcomes despite chemotherapeutic and surgical advances. Precision oncology strategies have been developed to treat EOCs characterized by BRCA1 and BRCA2 inactivation with consequent homologous recombination (HR) repair defects. HR deficiency enhances tumor sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), approved for EOCs as maintenance therapy, although they have been discontinued as recurrent EOC monotherapy. However, combination treatment with PARPis may be a viable alternate strategy for EOCs. Moreover, EOC patients with wild-type BRCA are ineligible for PARPs, necessitating novel approaches. We previously discovered that inhibiting Aurora kinase A (AURKA) downregulates PARP and BRCA1/2 expression in EOCs and may constitute a viable approach for EOCs.

Methods: Herein, we evaluated combined PARPi olaparib with the selective AURKA inhibitor (AURKAi) VIC-1911 in six different patient-derived xenograft (PDX) EOC models, including two with mutant BRCA1, two with mutant BRCA2, one with mutant BRCA1/2, and one with wild-type BRCA1/2.

Results: We found that combined olaparib + VIC-1911 treatment reduced tumor volumes and weights by up 90% in some PDX models, with synergistic effect compared to olaparib and VIC-1911 monotherapy. Additionally, combined olaparib + VIC-1911 treatment improved survival of mice harboring both mutant BRCA1 and wild-type BRCA1/2 PDXs. Generally, mice tolerated the drug combinations well during treatment, though loss of body weight was observed at higher drug dosages and with intensive treatment regimens.

Conclusion: Our studies indicate a synergistic benefit from combined PARPi and AURKAi in mutant and wild-type BRCA EOC tumors.