title: Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.
abstract: Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although 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. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical 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 show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status.
  
  
  CONCLUSIONS
  Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials.
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute;
authors.forename: Annan
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: N V
authors.initials: NV
authors.lastname: Rajeshkumar
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute;
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yabuuchi
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute;
authors.forename: Brian M
authors.initials: BM
authors.lastname: Alexander
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona; Departments of.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.affiliation: Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute; alec_kimmelman@dfci.harvard.edu.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D006801:Humans; D019656:Loss of Heterozygosity; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53