Concurrent Genomic Deletions Impact the Response to PARP Inhibition in Prostate Cancer
Abstract
Metastatic castration-resistant prostate cancer (CRPC) is an incurable disease that is expected to account for about 31,000 deaths each year in the United States. There are limited therapeutic options for metastatic CRPC patients that extend life. There is an urgent need for developing novel targeted therapies, especially personalized medicine, based on tumor genetic testing. Recent genomic studies have revealed a variety of actionable molecular targets with underlying genomic alterations. Notably, alterations in genes involved in DNA damage repair are among the most common genetic events and enriched in metastatic CRPC. These alterations have been correlated with particular therapeutic vulnerabilities in prostate cancer (PCa). Specifically, defects in homologous recombination (HR) DNA repair would predict sensitivity to inhibition of Poly (ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis) are a new type of targeted therapy, which works by preventing the enzyme PARP from repairing damaged DNA in tumor cells. BRCA1 and BRCA2 are the two genes encoding proteins essential for HR DNA repair. Therefore, cancer cells lacking BRCA1/2 depend instead on PARP-regulated DNA repair and are hypersensitive to PARP inhibition. The U.S. FDA has approved two PARP inhibitors (olaparib and rucaparib) for treatment of metastatic CRPC patients with deleterious BRCA1 and BRCA2 mutations based on the results from recent clinical trials. One of the major barriers to effective treatment using PARPis is how to select patients who most likely benefit from PARP inhibition. BRCA1/2 mutations can predict the response to PARPis with a high degree of accuracy. However, the degree to which patients with non-BCRA1/2 genomic alterations respond to PARPis remains unclear. Through a functional genome screening approach, we have recently discovered that loss of RNASEH2B gene in PCa cells predict the response to PARP inhibition. More importantly, genomic analyses have revealed that there are about 12% CRPC patients with focal genomic deletion on chromosome 13q harboring RNASEH2B and RB1. We found that loss of RNASEH2B alone sensitizes cells to PARP inhibition, while co-loss with RB1 renders cells resistant to PARPis again. However, this can be overcome by the combination treatment with ATR inhibition, which is another targeted therapy currently under clinical investigation. Objective/Aims of the Application: Our overall objective is to identify patients who most likely benefit from PARP inhibition beyond those harboring BRCA1/2 mutations. In this project, we will determine to what extent a short deletion (harboring RNASEH2B) or a long deletion (harboring both RNASEH2B and RB1) on chromosome 13q predicts the response to PARP inhibition in PCa. We will determine how RB1 loss affects PARPi sensitivity. Accordingly, we will determine whether and how ATR inhibition overcomes PARPi resistance caused by RB1 loss. The successful completion of this project will set the stage for a clinical trial in PCa patients with focal genomic deletion on chromosome 13q (occur in ~12% CRPC tumors) and significantly expand the pool of eligible patients for PARP and ATR inhibition either individually or in combination. Applicability of the Research: In this project, we will establish novel predictive biomarkers for targeted therapies with PARPi and ATRi in PCa. Loss of RNASEH2B alone predicts the response to PARPi, while co-loss of RNASEH2B/RB1 requires a therapy with PARPi in combination with ATRi. Both PARPi and ATRi are currently under clinical investigation. Our results will have a positive impact on ongoing trials with the goal of identifying more eligible patients and improving treatment options for men with incurable CRPC. Current clinical application of PARP inhibition is largely based on the genetic alterations of BRCA1 and BRCA2. The results from this project will support a new clinical trial to include a more comprehensive genomic analys
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210477
Entities
People
- Jia Li
Organizations
- United States Army