Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of p53, we demonstrate that while genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. Additionally, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Lastly, a mouse pre-clinical trial using cohorts of genetically characterized patient derived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together our data support the critical role of autophagy in pancreatic cancer and that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status.

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