title: Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma.
abstract: Targeting of pathways downstream of RAS represents a promising therapeutic strategy for pancreatic cancer, the fourth leading cause of cancer-related death in the USA, since activation of the Raf-MEK-ERK and PI3K-AKT pathways is found frequently in this disease and is associated with poor prognosis. Taking advantage of a panel of human PDAC cell lines and specific inhibitors of PI3K and/or mTOR, we systematically address the question whether dual-targeted inhibition of the PI3K and mTOR pathways offers advantages over single-targeted inhibition of PI3K in PDAC. We observe greater overall susceptibility of cell lines to dual inhibition compared to targeting PI3K alone. However, we find that dual inhibition of PI3K and mTOR induces autophagy to a greater extent than inhibition of each target alone. In agreement with this, we show that combined administration of PI3K/mTOR and autophagy inhibitors results in increased anti-tumor activity in vitro and in vivo in models of pancreatic adenocarcinoma. XL765, a PI3K/mTOR inhibitor used in our in vivo studies, is currently undergoing clinical evaluation in a variety of cancer types, while the autophagy inhibitor chloroquine is a widely used anti-malaria compound. Thus, our studies provide rationale for clinical development of combinations of these compounds for the treatment of pancreatic adenocarcinoma.
authors.affiliation: Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Olga K
authors.initials: OK
authors.lastname: Mirzoeva
authors.forename: Byron
authors.initials: B
authors.lastname: Hann
authors.forename: Yun K
authors.initials: YK
authors.lastname: Hom
authors.forename: Jayanta
authors.initials: J
authors.lastname: Debnath
authors.forename: Dana
authors.initials: D
authors.lastname: Aftab
authors.forename: Kevan
authors.initials: K
authors.lastname: Shokat
authors.forename: W Michael
authors.initials: WM
authors.lastname: Korn
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases