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PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets.
- Source :
-
Cancer research [Cancer Res] 2015 Apr 01; Vol. 75 (7), pp. 1399-412. Date of Electronic Publication: 2015 Feb 24. - Publication Year :
- 2015
-
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.<br /> (©2015 American Association for Cancer Research.)
- Subjects :
- 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 secondary
Mice, Knockout
Molecular Targeted Therapy
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases metabolism
Pyrimidines pharmacology
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Skin enzymology
Skin pathology
Skin Neoplasms drug therapy
Skin Neoplasms pathology
Melanoma enzymology
Protein Serine-Threonine Kinases physiology
Proto-Oncogene Proteins B-raf genetics
Skin Neoplasms enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 75
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 25712345
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-14-2785