Abstract 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 (FTIs), 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. Here, 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 (WT) RAS. 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.
Odeniyide et al. (Wed,) studied this question.