Understanding and targeting mutant splicing factors in pancreatic cancer

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer that is resistant to currently available therapies. Notably, we discovered that PDACs are exquisitely susceptible to a range of therapies directed at RNA splicing. However, it is unknown how alterations in RNA splicing drive PDAC tumorigenesis or impact therapeutic responses. Thus, identification of the role of aberrant RNA splicing in PDAC tumorigenesis could reveal novel therapeutic targets for PDAC. Our long-term goal is to identify, design, and test novel mechanistic-based targeted therapies for highly aggressive tumors such as PDAC. The main objective of this proposal is to characterize the role of RNA splicing factor mutations in PDAC pathogenesis and treatment response. Recently, we identified that the most common gain-of-function driver mutations found in 50% of PDACs (mutant KRAS and p53) synergize and cooperate through altered RNA splicing. While >90% of PDAC cases harbor mutant KRAS, only 50% co-occur with mutant p53. We performed mutual exclusivity analysis among hundreds of annotated mutations in PDACs and identified two mutant splicing factors, SF3B1 and RBM10, that co-occur with mutant KRAS but do not co-occur with mutant p53 and are mutually exclusive between each other. Additionally, our proof-of-concept studies using newly generated genetically engineered mouse models, oligo-therapy and RNA splicing inhibitors demonstrated that RNA splicing is a therapeutic target. Our central hypothesis is that persistent RNA splicing defects, downstream of SF3B1 and RBM10 mutations, are a required adaptive mechanism for KRAS-mediated tumorigenicity and represent a therapeutic target for PDAC. We aim to 1) determine the role of aberrant RNA splicing in PDAC tumorigenesis, 2) identify the function and correct RNA splicing defects in pancreatic cancer, and 3) evaluate the impact of mutant RNA splicing factors on the therapeutic efficacy of spliceosome inhibitors and chemotherapeutic agents. Our expected outcomes include identification of 1) how aberrant RNA splicing underlies major cancer-driving events, 2) novel therapeutic targets for our newly generated oligo-therapy or small molecule inhibitors, and 3) a previously overlooked mechanism for how cancer can evolve through multiple mutations converging at a common mechanistic function. We will use innovative newly generated genetically engineered mouse models co-expressing KRAS and splicing-factor mutations in the pancreas leading to autochthonous PDAC resembling patient tumors, and we will employ novel computational and genetic biotechnologies to identify and correct RNA splicing defects. These results will uncover a fundamental, yet novel non-mutational mechanism required for PDAC pathogenesis: altered RNA splicing. This will provide a strong basis for future approaches to treat PDAC, which would significantly impact personalized therapies and patient outcomes. This research directly aligns with NCI’s mission to advance scientific knowledge of drivers and targets of cancer to improve patient’s lives.