Targeting oncogenic HRAS in pediatric rhabdomyosarcoma

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, and RAS pathway mutations are known driver in majority fusion-negative (FN) RMS. Recent studies have demonstrated that HRAS enriched infant cases FN-RMS can be associated with an aggressive clinical course inferior outcomes. Using HRAS-mutant RMS cell lines xenograft models, we tipifarnib (farnesyl transferase inhibitor, FTI) decreases ERK signaling, vitro proliferation, vivo tumor growth. The effects incomplete, however, leading only to partial or short-lived responses. Limitations may due adaptive acquired resistance, suggesting HRAS-mutated sensitive inhibition combination therapy prevents delays emergence resistance. Trametinib (MEKi) inhibits growth models but has modest activity as a single agent, potentially release negative feedback activation upstream signaling. efficacy FTI MEKi not been previously explored RAS-driven FN-RMS. Materials Methods: We examined transcriptional using bulk RNA-sequencing identify therapeutic vulnerabilities exploited by RAS-directed therapies. Additionally, utilized cellular proliferation assays, soft agar colony-forming immunoblot evaluate trametinib on growth, differentiation, signaling via effector pathways. Results: Analysis RNA sequencing data revealed downregulation output genes upon treatment tipifarnib, confirming critical role MEK-ERK mediating response farnesyltransferase inhibition. We, therefore, tested observed additive dose-dependent 2D 3D combination. In cells, more potently reduced phosphorylation than either drug individually, indicating effective found induced myosin heavy chain expression lines, both promotion myogenic differentiation. Conclusions: Our suggest MEK inhibitor active HRAS-driven represent strategy for genomically-defined subset patients No conflict interest.