Abstract 498: In melanoma, disruption of the NF1/SPRED1 RAS inactivating complex cooperates with mutant KIT necessitating combined KIT and MEK inhibition to suppress tumor growth

Abstract We previously identified concurrent loss of function mutations of either NF1 or SPRED1 with activating mutations in KIT in primary acral and mucosal melanomas. We hypothesized the positive selection for NF1 or SPRED1 inactivation in the context of KIT mutations reflects a functional cooperation that may impact response to therapy targeting KIT. We find that contrary to each of the alterations alone, combined loss of either NF1 or SPRED1 in the presence of mutant KIT transforms immortalized mouse melanocytes. Because loss of NF1 and SPRED1 each activates RAS acting downstream of KIT, it could subvert the effect of KIT inhibitors. In patient-derived melanoma cell lines with KIT mutations and loss of NF1 or SPRED1, combination treatment with a KIT inhibitor (imatinib or avapritinib) and a MEK inhibitor (trametinib) acted synergistically. Combined KIT and MEK inhibition also reduced tumor growth and prolonged survival of mice xenografted with KIT-mutant melanoma cell lines. Our findings suggest that combination therapy with KIT and MEK inhibitors would be beneficial for melanoma patients with activating KIT mutations and concomitant loss of function NF1/SPRED1 mutations. Citation Format: Meng Kian Tee, Jia Yang, Jiafang Ma, Meng Wang, Dirk Schadendorf, Boris C. Bastian, Iwei Yeh. In melanoma, disruption of the NF1/SPRED1 RAS inactivating complex cooperates with mutant KIT necessitating combined KIT and MEK inhibition to suppress tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 498.