Overcoming PARP Inhibitor Resistance of BRCA-Deficient Ovarian Cancers
Abstract
BRCA1 and BRCA2 are critical DNA repair proteins involved in the maintenance of DNA by allowing cells to overcome stress (i.e., when something goes wrong during DNA replication) during DNA duplication (required for cells to divide and survive). Indeed, BRCA1/2 will stabilize the DNA through the disabled replication process and allow DNA repair by the enzyme called Poly ATR-ribose polymerase (PARP). Once the DNA is repaired, it can continue its replication process and the cell will keep living. BRCA1/2 mutations are prevalent in ovarian cancer, leading to genomic instability and providing a unique opportunity for targeted therapy. Due to their inability to cope with replication stress, BRCA1/2-deficient cancer cells are highly sensitive to inhibitors of PARP (PARPi), which specifically interfere with the repair of DNA single-strand breaks, which leads to the formation of DNA double-strand breaks and consequent cell death. Three PARPi (olaparib, niraparib, racaparib) have been approved by the FDA for the treatment of advanced ovarian cancer patients with BRCA mutations and shown significant efficacy. However, the vast majority of patients eventually developed resistance and relapsed. Therefore, a better understanding of how BRCA-deficient ovarian cancer cells acquire resistance to PARPi and how to overcome the resistance is urgently needed. We have gathered preliminary results suggesting that PARPi resistance of BRCA-deficient ovarian cancer cells is caused by an enzyme called ATR, which is a master checkpoint of DNA metabolism. These results led us to hypothesize that ATR inhibition is a unique strategy to overcome the PARPi resistance of ovarian cancer patients. In this project, we will systematically address three key aspects of the hypothesis. In Aim 1, we will identify the specific alterations in DNA repair pathways driving PARPi resistance. In Aim 2, we will elucidate how ATR regulates DNA replication. In Aim 3, we will test the efficacy of the ATRi-PARPi combination therapy in ovarian cancer patients resistant to PARPi. These studies may provide a solid basis for the use of ATR inhibitors in ovarian cancer treatment, and significantly improve the efficacy of PARP inhibitors in ovarian cancer therapy. If successful, this study could provide a new therapeutic option for patients whose tumors have progressed during PARPi treatment. Further, the combination of ATRi and PARPi may become the standard initial therapy for HRD tumors with resultant improved disease-free intervals.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810157
Entities
People
- Michael Birrer
Organizations
- United States Army
- University of Alabama at Birmingham