Journal
PLOS GENETICS
Volume 13, Issue 7, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1006913
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Funding
- National Cancer Institute [1R01CA15151301, P30CA062203, 1R01CM67967]
- National Institute of Arthritis and musculoskeletal and Skin Disease [1R01AR063116]
- American Cancer Society [RSG-11-128-01-CSM]
- Graduate Research fellowship from the National Science Foundation [DGE-1321846]
- Ford Foundation National Academies of Science, Engineering, and Medicine Dissertation Fellowship
- Stanley Behrens Fellowship
- Adeleson Medical Research Foundation
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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.
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