title: PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma.
abstract: The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPR-dependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for BrafV600E-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against BrafV600E-dependent tumors highlighting the clinical value of targeting PERK.
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Pytel
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mackiewicz
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Yuliya V
authors.initials: YV
authors.lastname: Katlinskaya
authors.affiliation: Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center dc1104, Indianapolis, Indiana, United States of America.
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Staschke
authors.affiliation: Oncology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center dc1104, Indianapolis, Indiana, United States of America.
authors.forename: Maria C G
authors.initials: MC
authors.lastname: Paredes
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Shuo
authors.initials: S
authors.lastname: Qie
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Olga S
authors.initials: OS
authors.lastname: Chajewski
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Lawrence
authors.identifier: http://orcid.org/0000-0002-8013-1275
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland.
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Majsterek
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
authors.affiliation: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000473:pathology; D018628:Gene Dosage / Q000235:genetics; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054852:Small Molecule Libraries / Q000008:administration & dosage; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D056811:Unfolded Protein Response / Q000235:genetics; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D054852:Small Molecule Libraries; D025521:Tumor Suppressor Proteins; C482119:BRAF protein, human; C460640:EIF2AK3 protein, human; D048493:Proto-Oncogene Proteins B-raf; D019892:eIF-2 Kinase