Combined Inhibition of HRAS and MEK Induces Tumor Regression and Restores Myogenic Differentiation in HRAS-Mutant Rhabdomyosarcoma

Hyperactive RAS signaling, induced by mutations in NRAS, HRAS, or KRAS, drives tumorigenesis in most PAX3/7::FOXO1 fusion-negative rhabdomyosarcomas (FN-RMS). Despite the frequency of these mutations, indirect RAS pathway-directed therapies have been ineffective for RAS-driven RMS. Farnesyltransferase (FTase) inhibitors (FTI), such as tipifarnib, inhibit HRAS membrane localization and blunt RAS effector signaling, leading to an antitumor effect in HRAS-mutant FN-RMS preclinical models. However, the effect is not durable. In this study, we investigated the mechanisms of adaptive resistance that limit the activity of FTIs, revealing that response to FTIs was limited by adaptive feedback reactivation of ERK signaling and upregulation of wild-type RAS. The combination of HRAS suppression with FTI and MEK inhibition impaired ERK reactivation and reduced ERK transcriptional output in HRAS-mutant RMS models. Cotargeting FTase and MEK restrained tumor progression and induced terminal myogenic differentiation. These findings highlight an effective combinatorial strategy and support its preclinical translation for patients with HRAS-mutant RMS. Significance: Farnesyltransferase and MEK inhibition suppresses ERK reactivation, decreases tumor growth, and promotes myogenesis in HRAS-mutant rhabdomyosarcoma.