Targeting MTOR signaling in pancreatic cancer

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Abstract Pancreatic cancer is a leading cause of cancer-related deaths in the United States with an estimated 48,000 deaths in 2021. Prior work has identified several commonly occurring genetic alterations, including activating KRAS mutations in approximately 95% of pancreatic ductal adenocarcinoma (PDAC) cases and these alterations are believed to be initiating lesions in the disease. Studies in inducible KRAS mouse models, as well as in human cancer cell lines, indicate that KRAS is an important therapeutic target in this disease. Yet, small molecule inhibitors of the most common KRAS mutants in PDAC are lacking. Therefore, other therapeutic strategies that target critical downstream molecules are required. Prior published work from our laboratory indicated that the kinase MTOR may be one such target. MTOR exists in two distinct signaling complexes – MTORC1 and MTORC2. Genetic ablation of the essential MTORC2 component Rictor impaired the development and progression of precursor PanIN lesions. Moreover, Rictor deletion extended survival in a genetically engineered mouse model (GEMM) of invasive PDAC. These observations raise the question of whether the inactivation of MTORC2 signaling in established invasive PDAC will impair their progression and/or stimulate their regression. The published observations also indicate that a deeper understanding of the signaling pathways regulated by the MTOR signaling complexes, and the resulting proteomic and gene expression changes, is required to effectively target this axis and to predict potential resistance mechanisms. This application therefore seeks to elucidate the roles of MTOR signaling in PDAC in vivo; to identify the proteomic and gene expression changes induced downstream of MTOR; and to investigate the efficacy of novel MTOR inhibitor-based combination therapeutic approaches. To achieve these goals, three specific aims are proposed. Using elegant and novel dual recombinase mouse models, studies in Aim 1 will investigate whether genetic inactivation of MTORC2 impairs the progression of established PDAC in vivo. Using single cell RNA sequencing after the acute genetic inactivation of MTORC2, the molecular consequences of impairing this signaling complex in vivo will be uncovered. The proposed studies in Aim 2 will identify the gene expression and proteomic changes induced following the inhibition of MTORC1, MTORC2 or both complexes in human PDAC cell lines. Computational integration of these datasets will lead to the identification of critical pathways and transcription regulators, which will then be functionally validated in human PDAC cell lines. Finally, studies in Aim 3 will interrogate the efficacy of novel combination therapy strategies based on MTOR inhibitors in human tumor organoids and credentialed GEMMs. The successful execution of the proposed studies will enhance the understanding of the role played by MTOR signaling during pancreatic tumorigenesis and enhance our ability to effectively target this pathway for PDAC therapy.