Overcoming PARP Inhibitor Resistance by Targeting the ATR-CHK1 Pathway in BRCA 1/2-Deficient Ovarian Cancer
Abstract
Cells in our body undergo DNA damage greater than a thousand times per day. BRCA1 and 2 (BRCA) are proteins that repair DNA damage. Mutations in the BRCA gene lead to increased DNA damage, in particular, DNA breaks increasing one s risk for developing OVCA. About 50% of all high-grade serous ovarian cancers (which is the most common type of ovarian cancer) have defects in repair of DNA damage. Thus, developing novel strategies to block DNA repair is a rational approach to bring new therapies to women with ovarian cancer. Poly(ADPribose) polymerase inhibitors (PARPi) are drugs that further block the cells ability to repair DNA breaks, making BRCA mutant cells especially more sensitive to PARPi, which is defined as synthetic lethality. Because of their anti-tumor activity, PARPi were recently approved by the Food and Drug Administration to treat BRCA1/2-deficient ovarian cancers. Response rates to PARPi are only ~30%-40% with no improved survival benefit demonstrated to date for BRCA 1/2 mutant ovarian cancer patients. Unfortunately, while they work to inhibit tumor growth, tumors ultimately become resistant to PARPi through incompletely understood mechanisms. Strategies to optimize therapeutic approaches capitalizing on synthetic lethality are needed and this proposal addresses this gap. Another approach to target DNA repair activity and improve therapeutic options in BRCA mutant ovarian cancers is to interfere with cell cycle checkpoint signaling. The ATR/CHK1 signaling pathway is another pathway that repairs DNA damage. ATR/CHK1 inhibitors prevent cells from arresting their growth to repair DNA damage, resulting in cell death. ATR/CHK1 inhibitors may be as effective or better than PARPi capitalizing on synthetic lethality for BRCA mutant ovarian cancers. Most ovarian cancers (>99%) have p53 mutations and a subset (~30%) have increased cyclin E expression. ATR/CHK1 inhibitors have also been shown to be synthetically lethal in cells with p53 mutations and overexpression of cyclin E. Thus, ATR/CHK1 inhibitors may have a role in both ovarian cancer patients with and without the BRCA1/2 mutation. There are new ATR and CHK1 inhibitors that are in early clinical trial development for cancer patients and have yet to be well explored in ovarian cancer patients. We hypothesize that ATR/CHK1 inhibitors may be equally or more effective than PARPi as a primary treatment option for BRCA1/2 mutant cancers. We also hypothesize that we can reverse PARPi resistance by targeting the ATR/CHK1 axis. By evaluating patient tumor biopsies pre- and post-PARPi, we expect to identify additional mechanisms of resistance in an pilot study. The goal of this proposal is thus to determine if ovarian BRCA mutant cancers can be treated by targeting the ATR/CHK1 pathway alone or in combination with PARPi, or be used secondarily following the development of PARPi resistance. We have preliminary data that ATR and CHK1 inhibitors may be as effective as PARPi in BRCA mutant cells and in a novel BRCA2 mutant mouse model. In addition, we show that combining PARPi with either CHK1 or ATR inhibitors is more effective in killing cells than PARPi alone. Finally, we found that the CHK1 pathway is activated in PARPi-resistant cells and CHK1 inhibitors are able to kill these resistant cells. We have developed novel experimental cell line and mouse models to study mechanisms of resistance and treatment response in BRCA mutant ovarian cancers. In our laboratory, we are developing primary tumor cell cultures from patients tumors collected at the time of surgery to be able to better study the unique biology of each patient s tumor. In addition, we have developed a patient-derived xenograft (PDX) model. We transplant a patient s ovarian tumor from surgery to the ovaries of approximately five mice. The mice develop ovarian tumors similar to the original patient tumor in terms of biology and response to treatments. The mice serve as avatars
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610399
Entities
People
- Fiona Simpkins
Organizations
- United States Army
- University of Pennsylvania