Seminar: Targeting MTOR signaling in pancreatic cancer
|Date/Time:||Tuesday, 28 Sep 2021 from 4:10 pm to 5:00 pm|
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Join this webinar to hear from Brian Lewis of the Department of Molecular, Cell and Cancer Biology at University of Massachusetts Medical School.
Synopsis: Pancreatic cancer is the most lethal malignancy, with a 5-year survival rate of 10% and median survival of less than one year. Activating mutations in the KRAS oncogene are a hallmark of this malignancy, occurring in 95% of cases. Prior work has shown that KRAS mutants efficiently drive the initiation of pancreatic cancer in vivo and that many established tumors remain dependent on sustained KRAS activity. Thus, targeting KRAS activity is a logical therapeutic strategy for pancreatic cancer. While progress has been made, direct targeting of KRAS remains a challenge. Therefore, identifying key downstream factors is of great importance. The serine/threonine protein kinase MTOR is a central regulator of cellular metabolism, growth and survival. We show that MTOR signaling complexes are required for the initiation of pancreatic tumorigenesis and efficient tumor progression in vivo. Disruption of MTOR signaling results in cell cycle arrest and the onset of a senescence-like phenotype. Moreover, treatment with MTOR inhibitors significantly extends survival in tumor-bearing mice. Interrogation of small molecule libraries identified additional compounds that cooperate with a MTOR kinase inhibitor to reduce the viability of pancreatic cancer cells in culture. Collectively, these findings identify MTOR as a critical factor downstream of KRAS in pancreatic cancer as well as a potential therapeutic target in this disease.