Abstract

Individuals with neurofibromatosis type 1 develop RAS-MAPK-MEK driven nerve tumors called neurofibromas. While MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in NF1 patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents SOS1 interaction with KRAS-GDP, interfering with the RAS-MAPK cascade upstream of MEK. Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1fl/fl mouse model of plexiform neurofibroma, but PK-driven combination of Selumetinib with BI-3406 significantly improved tumor parameters. Tumor volumes and neurofibroma cell proliferation, reduced by MEK inhibition, were further reduced by the combination. Neurofibroma are rich in Iba1+ macrophages; combination treatment resulted in small and round macrophages, with altered cytokine expression indicative of altered activation. The significant effects of MEKi plus SOS1 inhibition in this pre-clinical study suggest potential clinical benefit of dual targeting of the RAS-MAPK pathway in neurofibromas.

Significance Statement Interfering with the RAS-MAPK cascade upstream of MEK, together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas.