Kinome profiling of HRAS Q61K mutant SMS-CTR rhabdomyosarcoma cell line treated with tipifarnib

Hyperactive RAS signaling drives tumorigenesis in PAX 3/7::FOXO1 fusion-negative rhabdomyosarcoma (FN-RMS). Despite the frequency of these mutations, 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 FTI 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. Here, kinome profiling was performed on the SMS-CTR(HRAS Q61K) RMS cell line after 24 or 48 hour exposure to 100 nM tipifarnib.