Phosphoinositide-dependent kinase-1 (PDK-1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and PKC, and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significantly higher in primary melanoma, compared with nevi, and was further increased in metastatic melanoma. Selective inactivation of Pdk1 in the melanocytes of BrafV600E::Pten-/- or BrafV600E::Cdkn2a-/-::Pten-/- mice delayed the development of pigmented lesions and melanoma induced by systemic or local administration of 4-HT. Melanoma invasion and metastasis were significantly reduced or completely prevented by Pdk1 deletion. Administration of the PDK1 inhibitor GSK2334470 (PDKi) effectively delayed melanomagenesis and metastasis in BrafV600E::Pten-/- mice. Pdk1-/- melanomas exhibit a marked decrease in the activity of AKT, p70S6K and PKC. Notably, genetic inactivation or pharmacological inhibition of PDK1 were even more effective in attenuating melanoma development and metastasis of human tumors with Pten WT as in genetic model of BrafV600E::Cdkn2a-/-::Pten+/+ mice, representing an additional fraction of human tumors harboring such mutation. Gene expression analyses identified Pdk1-dependent changes in FOXO3a-regulated genes and inhibition of FOXO3a restored proliferation and colony formation of Pdk1-/- melanoma cells. PDK1 effect on FOXO3a and melanoma development and progression appears to be AKT independent. Our studies provide direct genetic evidence for the importance of PDK1, in part through FOXO3a-dependent pathway, in melanoma development and progression.
Citation Format: Marzia Scortegagna, Chelsea Ruller, Yongmei Feng, Rossitza Lazova, Harriet Kluger, Jian-Liang Li, Surya K. De, Robert Rickert, Maurizio Pellecchia, Marcus Bosenberg, Ze'ev Ronai. PDK1 in melanoma development and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 59. doi:10.1158/1538-7445.AM2014-59