Novel Mechanisms of Resistance to B-RAF Inhibitors in Melanoma.

摘要

The high level of exposure of our troops to UV radiation increases their risk of melanoma, the deadliest form of skin cancer. The major genotype in melanoma are mutant BRAF (40-60%) and mutant NRAS (15-20%). Significant advances have been made in the understanding of mutant BRAF melanoma leading to the FDA-approval of the RAF inhibitor PLX4032/Vemurafenib/zelboraf. By contrast, mutant NRAS melanomas are non-responsive to Vemurafenib. Hence, treatment options for mutant NRAS melanomas are reliant on standard chemotherapies and immunotherapies, which have low response rates and high toxicity. Directly targeting RAS has not proven to be clinically effective in RAS-driven tumors. In this proposal, we will focus on downstream RAS effectors. Furthermore, since resistance to monotherapies is evident in melanoma and other tumor types, we will apply a combinatorial approach to simultaneous block multiple arms of mutant NRAS-mediated signaling. Specifically, we hypothesize that TANK-binding kinase 1 (TBK1) mediates cell survival in mutant NRAS melanomas and that targeting TBK1, in combination with the distinct RAS-regulated MEK-ERK1/2, will promote cytotoxicity and reduce mutant NRAS melanoma growth. In sum, this proposal will utilize an innovative in vivo reporter system and aims to identify novel mechanisms of resistance in melanoma. At the completion of the proposed experiments, the identification of novel resistance-promoting mechanisms in mutant B-RAF melanomas will have a profound impact on future RAF inhibitor clinical trial strategies for both military personnel and the general public.