The RhoJ-BAD signaling network: An Achilles' heel for BRAF mutant melanomas

• Published in: PLoS genetics Vol. 13; no. 7; p. e1006913
• Main Authors: Ruiz, Rolando, Jahid, Sohail, Harris, Melissa, Marzese, Diego M, Espitia, Francisco, Vasudeva, Priya, Chen, Chi-Fen, de Feraudy, Sebastien, Wu, Jie, Gillen, Daniel L, Krasieva, Tatiana B, Tromberg, Bruce J, Pavan, William J, Hoon, Dave S, Ganesan, Anand K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.07.2017; Public Library of Science (PLoS)
• Subjects: Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; bcl-Associated Death Protein - biosynthesis; bcl-Associated Death Protein - genetics; Biology and Life Sciences; Cancer; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Clonal deletion; Deletion; Dermatology; Enzyme Inhibitors - administration & dosage; Funding; Gene Expression Regulation, Neoplastic - drug effects; Gene mutation; Genes; Genetic aspects; Genetic transformation; Health aspects; Humans; Kinases; Lasers; Medicine; Medicine and Health Sciences; Melanocytes; Melanocytes - drug effects; Melanocytes - pathology; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Metastases; Mutation; Neoplasm Metastasis; Nevus; Nevus - genetics; Nevus - pathology; p21-Activated Kinases - antagonists & inhibitors; p21-Activated Kinases - genetics; Proto-Oncogene Proteins B-raf - genetics; Research and Analysis Methods; rho GTP-Binding Proteins - genetics; Roles; Scholarships & fellowships; Signal transduction; Signal Transduction - drug effects; Software; Supervision; Transformation; Tumors; United States > US; California
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006913

Genes and pathways that allow cells to cope with oncogene-induced stress represent selective cancer therapeutic targets that remain largely undiscovered. In this study, we identify a RhoJ signaling pathway that is a selective therapeutic target for BRAF mutant cells. RhoJ deletion in BRAF mutant melanocytes modulates the expression of the pro-apoptotic protein BAD as well as genes involved in cellular metabolism, impairing nevus formation, cellular transformation, and metastasis. Short-term treatment of nascent melanoma tumors with PAK inhibitors that block RhoJ signaling halts the growth of BRAF mutant melanoma tumors in vivo and induces apoptosis in melanoma cells in vitro via a BAD-dependent mechanism. As up to 50% of BRAF mutant human melanomas express high levels of RhoJ, these studies nominate the RhoJ-BAD signaling network as a therapeutic vulnerability for fledgling BRAF mutant human tumors.