Regulation of LKB1 and AMPK Signaling by BRAF in Melanoma

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DESCRIPTION (provided by applicant): Mutations in the protein kinase BRAF have been found in ~70% of human melanoma. In preliminary studies, I have found that oncogenic BRAF V600E suppresses the activities of the tumor suppressor LKB1 and its downstream kinase AMPK through indirect phosphorylation on LKB1. Moreover, this inhibition is critical for the proliferation of melanoma cells with BRAF V600E mutation. The goal of this proposal is to fully understand the regulation of LKB1 and AMPK by BRAF signaling, examine its relevance in melanoma pathogenesis and explore its therapeutic implication. This proposal will define the molecular mechanism underlying the inhibition of LKB1-AMPK activity by BRAF V600E signaling, will investigate whether this inhibitory signaling mechanism is critical for melanoma cell proliferation, and tumor growth in mouse xenograft models, will examine the potential correlation between the active state of AMPK and ERK in human melanoma, will evaluate the effects of combined treatment of AMPK activators and MEK inhibitors on melanoma cell proliferation and xenograft tumor growth, and finally will characterize critical downstream signaling proteins of AMPK in melanoma. CANDIDATE: Bin Zheng received his Ph.D. in molecular pathology in 2002. His career goal is to become an independent scientist at an academic institution studying the signaling circuitry underlying melanoma pathogenesis, with an emphasis on the metabolic signaling and its translational therapeutic implications. He will receive advanced training in cancer biology with a focus on melanoma. Lewis Cantley, his sponsor, is an expert in lipid and protein kinase signaling, and its relevance in cancer and metabolic diseases. His scientific advisory committee includes Ronald DePinho, David Fisher, Lynda Chin, Scott Granter and John Asara, who are experts in cancer biology, melanocyte and melanoma biology, melanoma pathology and/or MassSpec. The sponsor, the advisory committee and the vibrant scientific environment in the Harvard Longwood Medical Area will facilitate Dr. Zheng in achieving his scientific and career goals. LAY SUMMARY: Melanoma is one of the most common and aggressive cancers, with ~60,000 new cases in the US in 2007. The goal of this research is to understand the regulation of the metabolic sensing LKB1-AMPK pathway by BRAF, one of the most frequently mutated genes in melanoma. This research will provide the molecular basis for future targeted therapies for melanoma.