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One or more keywords matched the following properties of Targeting Homologous Repair to Overcome Genotoxic Therapy Resistance in Pancreatic Cancer

abstract Current therapies such as radiation therapy (RT) or chemotherapy which target DNA (i.e. genotoxic) are largely ineffective at cancer control of pancreatic ductal adenocarcinoma (PDAC), sustaining this cancer type as a remarkably lethal and morbid disease. Novel strategies that increase the effectiveness while limiting toxicities of the current genotoxic therapies are critically needed. KRAS somatic mutations are the genetic hallmark of PDAC (90-95% in all PDACs), and are known to heighten a fundamental mechanism of cancer resistance: DNA repair. The most lethal type of DNA damage caused by RT and chemotherapy are double strand breaks (DSBs), and the ability of repairing DSBs is a major determining factor for the efficacy of these treatment modalities. Homologous recombination (HR) is a major mechanism to repair DSBs. Importantly, cancer cells with HR pathway deficiencies such as BRCA1/2 are susceptible to synthetic lethality with PARP inhibitors (PARPi), which inhibit single strand break (SSB) repair, due to lethal unrepaired DSBs. In our preliminary work, we found that (1) KRAS mutation increased transcription and translation of the DNA damage repair E3 ubiquitin ligase, RAD18; (2) RAD18 is highly expressed specifically in PDAC cells but not in the surrounding normal tissue or organs; (3) RAD18 expression was associated with poor disease survival; (4) RAD18 loss reduced BRCA-1 mediated HR repair, and (5) RAD18 loss increased PDAC cell response to genotoxic therapies. Therefore I hypothesize that RAD18 mediates KRAS-mutated PDAC resistance to genotoxic therapy and can be targeted to induce synthetic lethality of resistant PDAC (Fig 1). In the following aims, I propose to investigate the mechanism underlying the role of membrane-bound KRAS in regulating the nuclear DNA repair enzyme RAD18, a major promoter of DNA repair in PDAC that I have studied in my preliminary work. We further propose to carry out pathway analysis of the KRAS-RAD18-HR axis associated to therapy resistance, and investigate the effects of targeting RAD18 in combination with genotoxic therapies to induce synthetic lethality. The following aims are designed to increase mechanistic understanding of RAD18’s role in PDAC genotoxic resistance, and to provide insights about the translational feasibility of our proposed inducible synthetic lethality strategy.

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