OCRC Laboratory: Simpkins Lab
Combining PARP and ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nature Communications 2020 July 24; 11(1): 3726.
Summary: Resistance to chemotherapy is a major challenge in ovarian cancer. Most patients that initially respond to platinum-based chemotherapy will ultimately recur and will often become resistant to chemotherapy. A major focus of the Simpkins lab is to tackle the problem of drug resistance by using unique animal models that mimic the behavior of human tumors. Approximately 50% of high-grade serous ovarian tumors (the most common type of ovarian cancer) have defects in DNA repair capacity. This is often due to mutations in the BRCA1 or BRCA2 genes or other genes that work with the BRCA genes to repair DNA. PARP inhibitors were developed specifically to attack the vulnerability in DNA repair of BRCA mutant tumors. However, even treatment with PARP inhibitors ultimately results in the emergence of resistant tumors. The Simpkins lab showed that treatment with PARP inhibitors leads to activation of another DNA repair pathway that is dependent on a protein called ATR. Using the animal models developed in the lab, Dr. Simpkin’s group showed that blocking the activation of ATR with a specific ATR inhibitor, led to more effective tumor cell killing. Importantly, the combination of PARP inhibitor plus ATR inhibitor therapy led to more durable and complete responses in the animal models and was active in a variety of models with different genetic alterations. The results of this study paved the way for a clinical trial, called the CAPRI trial, that is assessing the efficacy of dual PARP and ATR inhibitors in women who have recurrent ovarian cancer.
