Journal article
Differential AKT dependency displayed by mouse models of BRAF V600E-Initiated melanoma
VM Durban, MM Deuker, MW Bosenberg, W Phillips, M McMahon
Journal of Clinical Investigation | Published : 2013
DOI: 10.1172/JCI69619
Abstract
Malignant melanoma is frequently driven by mutational activation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) accompanied by silencing of the phosphatase and tensin homology (PTEN) tumor suppressor. Despite the implied importance of PI3K signaling in PTENNull melanomas, mutational activation of the gene encoding the catalytic subunit of PI3Kα (PIK3CA), is rarely detected. Since PTEN has both PI3-lipid phosphatase-dependent and -independent tumor suppressor activities, we investigated the contribution of PI3K signaling to BRAFV600E-induced melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway-targeted inhibitors. These experiments revealed that mutationally..
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Awarded by National Cancer Institute
Funding Acknowledgements
We thank all members of the McMahon lab for advice and guidance on this project, especially Jillian Silva for permission to cite unpublished research. We thank Vincent Hearing (NIH) for supplying antisera against mouse melanocyte proteins and Tim McCalmont, Boris Bastian, Scott Kogan (UCSF), and the Center for Genomic Pathology for histopathological evaluation of mouse melanomas. We thank Adil Daud (UCSF) and Antoni Ribas (UCLA) for stimulating discussions on melanoma therapy, Meenhard Herlyn (Wistar Institute) for providing melanoma cell lines, and Glenn Merlino (NCI) for critical advice on the generation of mouse melanoma cell lines. We thank our colleagues in various biotechnology and pharmaceutical companies for providing the following compounds and information on their use: Steven Townson, Heike Keilhack and Ahmed Samatar for MK-2206 and SCH772984 (Merck Pharmaceuticals); Emmanuelle di Tomaso, Janet Lyle, and Darrin Stuart for BKM-120 (Novartis); Leisa Johnson and Lori Freedman for GDC-0941 (Genentech); and Tona Gilmer and Kirin Patel for GSK2118436 (GlaxoSmithKline). We thank Byron Hann and the Helen Diller Family Comprehensive Cancer Center's Pre-clinical Therapeutics Core for advice on xenograft implantation and drug administration to mice. This research was supported by grants from the Melanoma Research Alliance (to M. McMahon) and from the NIH/NCI CA176839 (to M. McMahon) and CA112054 (to M.W. Bosenberg) and by project grants from the National Health and Medical Research Council of Australia to W.A. Phillips.