Targeting Translesion Synthesis to Overcome PARP Inhibitor Resistance in Ovarian Cancer
Abstract
Ovarian cancer is the fifth deadliest cancer in women in the United States. Current standard treatment of ovarian cancer consists of surgery to remove tumors, followed by platinum- and taxane-based chemotherapy. Despite the recent advances in cancer treatment, long-term survival in epithelial ovarian cancer (EOC) patients has not significantly increased in the last 25 years. PARP is an enzyme that marks damaged DNA for repair. If PARP becomes stuck on the DNA, DNA replication in these cells is often stuck with the unwieldy PARP-DNA structure. Like a jammed zipper, this prevents the cancer cell from moving forward or accessing the DNA during replication. PARP inhibitors are drugs that intentionally jam the PARP-DNA machinery in order to kill cancer cells without hurting healthy cells. This process works predominantly on cancer cells that lack a specialized DNA repair mechanism, named “homologous recombination,” which requires BRCA1 and BRCA2, but luckily, BRCA mutations are relatively common in EOC. PARP inhibitors have been approved by the FDA to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations. It is also approved for use as prophylaxis to prevent relapse, and in certain instances, it is even used to treat cancers without BRCA mutations. This innovative drug is changing clinical practice in BRCA mutant EOC patients, and unlike traditional chemotherapies, it can kill cancer cells without causing devastating damage to healthy cells in the body. Unfortunately, most patients who receive PARP inhibitors eventually develop resistance to the drug, leading to eventual relapse. Understanding the cause of PARPi resistance is important for improving the experience and prognosis of EOC patients. In this study, we will investigate how translesion DNA synthesis (TLS) affects cancer cells’ ability to survive PARP inhibitor treatment and develop resistance. TLS is a DNA damage tolerance mechanism that can bypass DNA blockages with the aid of specialized, low-fidelity DNA polymerases. These error-prone DNA readers could be the reason why cancer cells become resistant to PARP inhibitors. If cancer cells can circumvent the blockages caused by PARP inhibitors, they will be able to successfully replicate their DNA without complications like double-strand breaks. Our recent studies have revealed that PARP inhibitor treatment can increase the expression of a TLS polymerase named Pol eta (encoded by POLH) in BRCA2-mutated ovarian cancer cell lines. In addition, reduction of Pol eta level in cancer cells can sensitize them to PARP inhibitors. Based on this scientific premise, we hypothesize that TLS reduces PARP inhibitor’s toxicity in cancer cells, and we predict that suppressing TLS can prevent resistance and relapse. Furthermore, we propose that the increased rates of mutation caused by TLS may promote the generation of additional mutations in BRCA, which interestingly, can actually restore BRCA activity and render PARP inhibitors ineffective. Thus, TLS could be a major contributor to PARP inhibitor resistance in BRCA1/2-mutated ovarian cancer; suppression of TLS could prevent PARP inhibitor resistance in ovarian cancer. In this project, we will explore how TLS affects the cellular response to the PARP-DNA blockages caused by PARP inhibitors. We will investigate whether inhibition of TLS can reverse intrinsic PARP inhibitor resistance in ovarian cancer, which involves bypassing DNA blockages. Then, we will determine whether inhibition of TLS can also prevent acquired PARP inhibitor resistance, which arises from BRCA reverse mutations that restore their activity for homologous recombination repair. In vitro cell culture and in vivo xenograft mouse models and a newly discovered TLS inhibitor will be used to test our hypothesis. We hope that at the conclusion of this project, we will have understood how trapped PARP-DNA complexes are bypassed by TLS. We will also have conclusive evidence of whether TLS con
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110287
Entities
People
- Qi-En Wang
Organizations
- Ohio State University
- United States Army