title: Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer.
abstract: Use of the inhibitor of ALK fusion onco-protein, crizotinib (PF02341066), has achieved impressive clinical efficacy in patients with ALK-positive non-small cell lung cancer. Nevertheless, acquired resistance to this drug occurs inevitably in approximately a year, limiting the therapeutic benefits of this novel targeted therapy. In this study, we found that autophagy was induced in crizonitib-resistant lung cancer cells and contributed to drug resistance. We observed that ALK was downregulated in the crizotinib-resistant lung cancer cell line, H3122CR-1, and this was causally associated with autophagy induction. The degree of crizotinib resistance correlated with autophagic activity. Activation of autophagy in crizotinib-resistant H3122CR-1 cells involved alteration of the Akt/mTOR signaling pathway. Furthermore, we demonstrated that chloroquine, an inhibitor of autophagy, could restore sensitivity of H3122CR-1 to crizotinib and enhance its efficacy against drug-resistant lung cancer. Thus, modulating autophagy may be worth exploring as a new strategy to overcome acquired crizonitib resistance in ALK-positive lung cancer.
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA; Department of Respiratory Medicine; The First Affiliated Hospital of Soochow University; Suzhou, Jiangsu, PR China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ji
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Patel
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Mian
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Shundong
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Medicine; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
authors.affiliation: Department of Pharmacology; Penn State Hershey Cancer Institute; The Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center; Hershey, PA USA.
authors.forename: Xingcong
authors.initials: X
authors.lastname: Ren
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D000077547:Crizotinib; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008819:Mice, Nude; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D002738:Chloroquine; C546842:MTOR protein, human; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases
keywords: ALK; autophagy; crizotinib; drug resistance; lung cancer