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Combined inhibition of HRAS and MEK induces tumor regression and restores myogenic differentiation in HRAS-mutant rhabdomyosarcoma

ABSTRACT: Hyperactive RAS signaling drives tumorigenesis in PAX 3/7::FOXO1 fusion-negative rhabdomyosarcoma (FN-RMS). Despite the frequency of these mutations, indirect RAS pathway-directed therapies have been ineffective for RAS-driven RMS. Farnesyltransferase (FTase) inhibitors (FTIs), such as tipifarnib, inhibit HRAS membrane localization and blunt HRAS effector signaling, leading to an antitumor effect in HRAS-mutant FN-RMS preclinical models. Response to FTase inhibition is limited by adaptive feedback reactivation of ERK signaling and upregulation of wild-type (WT) RAS. We found that the combination of HRAS suppression with FTI and MEK inhibition (MEKi) impaired ERK reactivation and reduced ERK transcriptional output in HRAS-mutant RMS models. Co-targeting 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312030 | GEO | 2025/12/08

REPOSITORIES: GEO

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