title: PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets.
abstract: Melanoma development involves members of the AGC kinase family, including AKT, PKC, and, most recently, PDK1, as elucidated recently in studies of Braf::Pten mutant melanomas. Here, we report that PDK1 contributes functionally to skin pigmentation and to the development of melanomas harboring a wild-type PTEN genotype, which occurs in about 70% of human melanomas. The PDK1 substrate SGK3 was determined to be an important mediator of PDK1 activities in melanoma cells. Genetic or pharmacologic inhibition of PDK1 and SGK3 attenuated melanoma growth by inducing G1 phase cell-cycle arrest. In a synthetic lethal screen, pan-PI3K inhibition synergized with PDK1 inhibition to suppress melanoma growth, suggesting that focused blockade of PDK1/PI3K signaling might offer a new therapeutic modality for wild-type PTEN tumors. We also noted that responsiveness to PDK1 inhibition associated with decreased expression of pigmentation genes and increased expression of cytokines and inflammatory genes, suggesting a method to stratify patients with melanoma for PDK1-based therapies. Overall, our work highlights the potential significance of PDK1 as a therapeutic target to improve melanoma treatment.
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Marzia
authors.initials: M
authors.lastname: Scortegagna
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Lau
authors.affiliation: Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, NCI, Bethesda, Maryland.
authors.forename: Tongwu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, Arizona.
authors.forename: Chris
authors.initials: C
authors.lastname: Sereduk
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, Arizona.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yin
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.affiliation: Department of Dermatology, Yale University, School of Medicine, New Haven, Connecticut. Department of Pathology, Yale University, School of Medicine, New Haven, Connecticut.
authors.forename: Katrina
authors.initials: K
authors.lastname: Meeth
authors.affiliation: Department of Dermatology, Yale University, School of Medicine, New Haven, Connecticut. Department of Pathology, Yale University, School of Medicine, New Haven, Connecticut.
authors.forename: James T
authors.initials: JT
authors.lastname: Platt
authors.affiliation: Department of Dermatology, Yale University, School of Medicine, New Haven, Connecticut. Department of Pathology, Yale University, School of Medicine, New Haven, Connecticut.
authors.forename: Casey G
authors.initials: CG
authors.lastname: Langdon
authors.affiliation: Department of Dermatology, Yale University, School of Medicine, New Haven, Connecticut.
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.affiliation: Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, NCI, Bethesda, Maryland.
authors.forename: Kevin
authors.initials: K
authors.lastname: Brown
authors.affiliation: Department of Pathology, Yale University, School of Medicine, New Haven, Connecticut.
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
authors.affiliation: Department of Dermatology, Yale University, School of Medicine, New Haven, Connecticut. Department of Pathology, Yale University, School of Medicine, New Haven, Connecticut.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California. ronai@sbmri.org.
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology* / Q000556:secondary; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012867:Skin / Q000201:enzymology / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017874:Immediate-Early Proteins; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D011743:Pyrimidines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000099184:Serum-Glucocorticoid Regulated Kinases; C555257:GSK 2334470; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; C532254:2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid; C482119:BRAF protein, human; C403243:SGK3 protein, human