PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets

Cancer Res. 2015 Apr 1;75(7):1399-412. doi: 10.1158/0008-5472.CAN-14-2785. Epub 2015 Feb 24.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzoates / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • G1 Phase Cell Cycle Checkpoints
  • Humans
  • Immediate-Early Proteins / metabolism
  • Indazoles / pharmacology
  • Lymphatic Metastasis
  • Melanoma / drug therapy
  • Melanoma / enzymology*
  • Melanoma / secondary
  • Mice, Knockout
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Pyrimidines / pharmacology
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Skin / enzymology
  • Skin / pathology
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / pathology

Substances

  • Benzoates
  • Bridged Bicyclo Compounds, Heterocyclic
  • GSK 2334470
  • Immediate-Early Proteins
  • Indazoles
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • 2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid
  • BRAF protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins B-raf
  • SGK3 protein, human
  • serum-glucocorticoid regulated kinase