Metabolic plasticity drives mechanisms of PARP inhibitor persistence in ovarian cancer

Ovarian cancer results in the death of 1 in 6 patients within the first three months of diagnosis, making it the fifth deadliest cancer in the United States. While clinicians have moved towards using targeted therapies, patients often stop responding to the treatment. In this study, we combined both experimental and computational techniques to explore this process by treating OVCAR3 cell line with Olaparib (a PARP inhibitor). We then performed single cell RNA sequencing on both naïve and persistent populations. RNA velocities analysis indicated that there was a trajectory of gene expressions adaptation toward the persister phenotype. To further investigate the persistence mechanism, metabolic pathways were scored on our single cell data, and persistence cells were found to have differentially expressed glutamine metabolism compared to naïve cells. To test these findings, both persistent and naïve cells where cultured in glutamine deprived media and we found persistent cells have higher viability than the naïve cells particularly under Olaparib treatment. We then found that these cells acquired glucose dependency that can be used as vulnerability. This finding suggested increased plasticity of cancer cells under long-term Olaparib treatment. We then built a math model that suggested treatment scheduling could be improved by considering metabolic plasticity in response to Olaparib treatment.