Format

Send to

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

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

Author information

1
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
2
Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, NCI, Bethesda, Maryland.
3
Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, Arizona.
4
Department of Dermatology, Yale University, School of Medicine, New Haven, Connecticut. Department of Pathology, Yale University, School of Medicine, New Haven, Connecticut.
5
Department of Dermatology, Yale University, School of Medicine, New Haven, Connecticut.
6
Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
7
Department of Pathology, Yale University, School of Medicine, New Haven, Connecticut.
8
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California. ronai@sbmri.org.

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.

PMID:
25712345
PMCID:
PMC4383687
DOI:
10.1158/0008-5472.CAN-14-2785
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center