Abstract IA24: Are there nonimmune targets in the BRAFV600 WT melanoma patient?

Abstract

Abstract Molecular targeting of melanoma beyond the BRAFV600 mutation has been a frustrating and largely unsuccessful pursuit. The dominant driver in many of these cases is the gain of function NRAS mutations, while a smaller subset are in part driven by NF1 loss of function genetic alterations, and lastly a subset (WT) with a variety of mutations, most of which activate the MAPK pathway such as mutations in c-Kit, MEK, KRAS, HRAS, and alternate non-V600 BRAF mutations. This effort has concentrated on the inhibition of the activated MAPK pathway with MEK inhibitors and targeted NRAS tumors, which make at least 1/3 of the non-BRAF V600 mutant melanoma. As a single agent this approach has been disappointing, but preclinical data support the need for combination therapy, including MEK inhibition with inhibition of alternate pathways such as the PI3/Akt pathway, the cell cycle pathway with CDK4/6 inhibitors, or MDM2 inhibitors to restore functional p53 driven apoptosis. These approaches have been frequently plagued by significant toxicity. Many of these approaches continue to be pursued in the clinic in the hope that different schedules will be more effective and less toxic. An obvious target has been inhibition of downstream pERK which has shown some limited clinical activity. Attacking other pathways looks promising, including targeting mitotic kinases, such as PLK1 and Aurora kinase A. Either inhibiting autophagy or enhancing Bim-directed apoptosis is also under investigation. Finally, we now have a better understanding about the interaction between the targeted agent and the tumor microenvironment. Preclinical and clinical studies show that MEK inhibition can actually enhance the T-cell response at the site of the tumor by selectively eliminating naïve T cells; CDK4/6 inhibition can influence PD-L1 expression and induce retroviral sequences, which then induce an inflammatory (hot) tumor microenvironment. On the other hand, there is further evidence that the microenvironment may be critical for targeted therapy to be effective. This supports an approach combining targeted agents with immune checkpoint inhibitors even in BRAF WT melanoma. While immunotherapy approaches dominate treatment of BRAF WT melanoma, it is critical that we do not lose focus on defining targets, developing better agents, and learning to administer them by an optimal schedule. Citation Format: Jeffrey A. Sosman. Are there nonimmune targets in the BRAFV600 WT melanoma patient? [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA24.