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
Department of Biological Chemistry, University of California, Irvine, Irvine, CA, United States of America.
Department of Dermatology, University of California, Irvine, Irvine, CA, United States of America.
PLoS Genet. 2017 Jul 28;13(7):e1006913. doi: 10.1371/journal.pgen.1006913. eCollection 2017 Jul.
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.
使细胞能够应对癌基因诱导应激的基因和信号通路是尚未被大量发现的选择性癌症治疗靶点。在本研究中，我们鉴定出一条RhoJ信号通路，它是BRAF突变细胞的选择性治疗靶点。BRAF突变黑素细胞中的RhoJ缺失可调节促凋亡蛋白BAD以及参与细胞代谢的基因的表达，损害痣形成、细胞转化和转移。用阻断RhoJ信号的PAK抑制剂对新生黑色素瘤肿瘤进行短期治疗，可在体内阻止BRAF突变黑色素瘤肿瘤的生长，并通过依赖BAD的机制在体外诱导黑色素瘤细胞凋亡。由于高达50%的BRAF突变型人类黑色素瘤表达高水平的RhoJ，这些研究将RhoJ-BAD信号网络确定为初发BRAF突变型人类肿瘤的治疗弱点。
