Alterations in the PTEN/AKT/PI3K and BRAF/MEK/MAPK signaling pathways play a central role in the development and progression of the majority of melanomas. Over 50% of human melanomas have inactivation of PTEN and upregulation of the AKT/phosphatidylinositol 3-kinase (PI3K) signaling pathways. Yet, while considerable effort is being devoted to the development of PI3K/AKT inhibitors as possible combinatorial therapies with the currently available BRAFV600E inhibitors, little attention has been paid to the potential therapeutic importance of 3-phosphoinositide-dependent protein kinase 1 (PDK1), a regulator of the AKT and PKC signaling pathways. Our preliminary results provide the first genetic evidence for the significance of PDK1 in melanoma development and progression, and provide the foundation for our hypothesis that PDK1 is an important regulatory component in melanogenesis and a novel target for melanoma therapy. Melanocyte-specific deletion of PDK1 in BrafV600E:Pten-/-:Pdk1-/- animals delayed the development of pigmented lesions and the onset of melanoma formation with concomitant and significant delay in lung and lymph node metastasis. Further, pharmacological PDK inhibitors also delayed melanomagenesis and metastasis. Gene expression analysis highlights a role for PDK1-FOXO signaling in melanomagenesis. TMA analysis identified high PDK1 expression in melanoma, but not nevi. We therefore propose to: (i) substantiate these initial observations in Nras and Braf mutan melanoma harboring WT Pten-models representing the vast majority of human melanomas, (ii) characterize the molecular mechanisms underlying PDK1 control of melanoma development and progression through mapping the AGC kinases affected by PDK1 and the role of PDK1 in tumor microenvironment as for select subpopulations of melanoma, (iii) identify biomarkers for PDK1- sensitive tumors and determine the clinical significance of PDK1 expression in melanoma, and (iv) develop and characterize effective combinatorial therapies involving PDK1 inhibitors to increase response and reduce treatment resistance. Our proposed studies provide an unprecedented opportunity to establish the importance of PDK1 in melanoma development and its potential as novel therapeutic modality.
Based on preliminary results that provide the first genetic evidence for the importance of PDK1, a regulator of the AKT and PKC signaling pathways in melanoma development and progression, we propose to establish its potential as novel therapeutic modality.
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