title: LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress.
abstract: Five-year survival rates for non-small cell lung cancer (NSCLC) have seen minimal improvement despite aggressive therapy with standard chemotherapeutic agents, indicating a need for new treatment approaches. Studies show inactivating mutations in the LKB1 tumor suppressor are common in NSCLC. Genetic and mechanistic analysis has defined LKB1-deficient NSCLC tumors as a phenotypically distinct subpopulation of NSCLC with potential avenues for therapeutic gain. In expanding on previous work indicating hypersensitivity of LKB1-deficient NSCLC cells to 2-deoxy-D-glucose (2DG), we find that 2DG has in vivo efficacy in LKB1-deficient NSCLC using transgenic murine models of NSCLC. Deciphering of the molecular mechanisms behind this phenotype reveals that loss of LKB1 in NSCLC cells imparts increased sensitivity to pharmacological compounds that aggravate ER stress. In comparison to NSCLC cells with functional LKB1, treatment of NSCLC cells lacking LKB1 with the ER stress activators (ERSA), tunicamycin, brefeldin A or 2DG, resulted in aggravation of ER stress, increased cytotoxicity, and evidence of ER stress-mediated cell death. Based upon these findings, we suggest that ERSAs represent a potential treatment avenue for NSCLC patients whose tumors are deficient in LKB1.
authors.affiliation: Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States. Electronic address: landon.inge@dignityhealth.org.
authors.forename: Landon J
authors.initials: LJ
authors.lastname: Inge
authors.affiliation: Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Friel
authors.affiliation: Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Richer
authors.affiliation: Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Fowler
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Whitsett
authors.affiliation: Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ, United States.
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
authors.affiliation: Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States.
authors.forename: Ross M
authors.initials: RM
authors.lastname: Bremner
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020126:Brefeldin A / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008279:Magnetic Resonance Imaging; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D014415:Tunicamycin; D020126:Brefeldin A; D003847:Deoxyglucose; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: ER stress; LKB1; Lung cancer; Treatment; UPR