UC Irvine

The main function of the mammalian skin is to protect the organism against various deleterious environmental factors such as UVR. The skin contains specialized pigment producing cells, known as melanocytes, to protect against UVR. However, when melanocytes acquire mutations from excessive exposure to UVR or other factors, they transform into melanoma. Melanoma is the deadliest type of skin cancer that invades neighboring tissue during early tumor development. The BRAF oncogene is mutated in over 50% of human melanoma cases and therapies that target the BRAF signaling are effective at inducing tumor regression. Unfortunately, melanoma tumors acquire resistance and become unresponsive to BRAF therapy because of alterations in various signaling networks. Genes and pathways that allow cells to cope with oncogene-induced stress represent selective cancer therapeutic targets that remain largely undiscovered. In addition, melanomas accumulate a high burden of mutations that could potentially generate neoantigens, yet somehow suppress the immune response to facilitate continued growth. In order to better understand the signaling networks that drive BRAF mutant melanoma, we identified a RhoJ signaling pathway that is a selective therapeutic target for BRAF mutant tumors. RhoJ is a small GTPase that cycles between an active-GTP bound state and an inactive-GDP bound state that regulates various physiological mechanisms. Previously we demonstrated that RhoJ is involved in chemoresistance in melanoma and in suppressing ATR activity. Using an autochthonous mouse model of melanoma, we determined that loss of RhoJ significantly prolonged the life of mice bearing BRAFV600E mutant melanomas by delaying tumor initiation and reducing metastasis. Transcriptome analysis revealed that RhoJ deletion in BRAF mutant tumors modulates the expression of the pro-apoptotic protein BAD as well as genes involved in cellular metabolism, generating tumors that grow more slowly and metastasize less avidly. PAK inhibitors induce apoptosis in melanoma cells in vitro via a BAD-dependent mechanism and induce the regression of BRAF mutant melanoma tumors in vivo. We also demonstrate that ATR mutant tumors accumulate multiple mutations and alter the immune system by decreasing T-cells to encourage tumor growth. Taken together, these studies identify the RhoJ-BAD signaling network as a therapeutic vulnerability for BRAF mutant tumors. Additionally, these studies also identify a novel mechanism by which melanoma cells modulate the tumor microenvironment to promote survival.