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 during DNA duplication. Indeed, BRCA1/2 will stabilize the DNA through the disabled replication process and allow DNA repair by the enzyme called PolyATR-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, rucaparib) 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. In this project, we will systematically address three key aspects of the hypothesis. In Aim1, 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2020
- Accession Number
- AD1132094
Entities
People
- Michael J. Birrer
Organizations
- University of Alabama at Birmingham