title: Inhibition of autophagy attenuates pancreatic cancer growth independent of TP53/TRP53 status.
abstract: Basal levels of autophagy are elevated in most pancreatic ductal adenocarcinomas (PDAC). Suppressing autophagy pharmacologically using chloroquine (CQ) or genetically with RNAi to essential autophagy genes inhibits human pancreatic cancer growth in vitro and in vivo, which presents possible treatment opportunities for PDAC patients using the CQ-derivative hydroxychloroquine (HCQ). Indeed, such clinical trials are ongoing. However, autophagy is a complex cellular mechanism to maintain cell homeostasis under stress. Based on its biological role, a dual role of autophagy in tumorigenesis has been proposed: at tumor initiation, autophagy helps maintain genomic stability and prevent tumor initiation; while in advanced disease, autophagy degrades and recycles cellular components to meet the metabolic needs for rapid growth. This model was proven to be the case in mouse lung tumor models. However, in contrast to prior work in various PDAC model systems, loss of autophagy in PDAC mouse models with embryonic homozygous Trp53 deletion does not inhibit tumor growth and paradoxically increases progression. This raised concerns whether there may be a genotype-dependent reliance of PDAC on autophagy. In a recent study, our group used a Trp53 heterozygous mouse PDAC model and human PDX xenografts to address the question. Our results demonstrate that autophagy inhibition was effective against PDAC tumors irrespective of TP53/TRP53 status.
authors.affiliation: Division of Genomic Stability and DNA Repair; Department of Radiation Oncology; Dana Farber Cancer Institute; Boston, MA USA.
authors.forename: Annan
authors.initials: A
authors.lastname: Yang
authors.affiliation: Division of Genomic Stability and DNA Repair; Department of Radiation Oncology; Dana Farber Cancer Institute; Boston, MA USA.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D006886:Hydroxychloroquine
keywords: Atg5; PDAC; TP53; Trp53; autophagy; chloroquine; pancreatic cancer