KRAS is required for plexiform neurofibroma formation and represents a targetable vulnerability in established tumors.

Abstract

Patients with neurofibromatosis type 1 develop Schwann cell tumors called neurofibromas that arise within peripheral nerves, driven by loss of neurofibromin and consequent increased RAS/RAF/MEK signaling. MEK inhibitors achieve partial responses for benign neurofibromas but are limited by toxicity and incomplete efficacy, necessitating alternative approaches. Using the <i>Dhh-</i>Cre;<i>Nf1</i>^fl/fl neurofibroma mouse model, we found that genetic ablation of <i>Kras</i>, but not <i>Hras</i>, markedly reduced neurofibroma development, inhibited MAPK activation, and rescued disrupted Remak bundles that are a morphologic hallmark of neurofibromas. These findings reveal a RAS paralog-specific requirement for KRAS in NF1-deficient neurofibroma initiation. Pharmacological KRAS inhibition with BI6674, an orally bioavailable KRAS^multi inhibitor, reduced tumor volume and proliferation in established neurofibromas and remodeled the tumor immune microenvironment, decreasing macrophages and dendritic cells. Combining KRAS and MEK inhibition further enhanced tumor regression. These findings demonstrate that KRAS is essential for neurofibroma formation and represents a promising therapeutic target, supporting clinical evaluation of KRAS inhibition for neurofibromas in patients with neurofibromatosis type 1.