Research Scholar (Senior Post-Doc)
Human Oncology & Pathogenesis Program
Memorial Sloan Kettering Cancer Center (MSKCC)
New York, NY
Targeting a novel mutant p53-Kras cooperation mechanism in pancreatic cancer
Overview
Aim: Cancer Therapy
Pancreatic cancer is currently the third leading cause of cancer death in the United States, in part because these tumors are highly resistant to chemotherapy. Pancreatic cancer commonly arises by mutations in KRAS and p53, however, these mutant proteins have proven to be very difficult to target. Therefore, there are intense efforts to identify druggable critical downstream targets required by these oncoproteins that could be leveraged to improve therapy. We have identified that p53 hotspot mutations rewire the splicing of mRNAs encoding GTPase activating proteins (GAPs) to promote maximal activation of KRAS. Through biochemical and functional experiments, we demonstrate that mutant p53 enforces expression of GAP isoforms that have defective membrane localization, promoting oncogenic RAS signaling in vitro and in vivo. This finding provides insight into the long unexplained observation of highly frequent co-occurrence of RAS and p53 mutations in pancreatic cancer. This project aims to 1) understand how p53 hotspot mutations alter RNA splicing of GAPs and advance our understanding of activating and inhibitory mechanisms of oncogenic KRAS, and 2) validate our findings that targeting the splicing machinery and correcting for GAP-splicing errors are therapeutic opportunities for pancreatic cancer treatment using primary-patient samples. We hope that these studies provide insights to develop novel biomarker-driven therapies for pancreatic cancer to improve patient survival.