Abstract B046: Pan-RAS Inhibition as a novel therapeutic strategy for RAS-driven rhabdomyosarcoma

Abstract Introduction: Oncogenic activation of RAS pathways, either through mutations in NRAS, KRAS or HRAS or through loss of function alterations in the RAS GTP-ase activating protein (RAS-GAP) NF1 are found in about 40% of fusion-negative rhabdomyosarcoma (FN-RMS). Attempts to indirectly inhibit RAS and RAS-effector signaling have been unsuccessful in RAS-driven FN-RMS. Daraxonrasib (RMC-6236) is a novel state-selective pan-RAS inhibitor (RAS(ON)i) that inhibits GTP-bound oncogenic and wild-type (WT) RAS. Daraxonrasib has demonstrated clinical activity in RAS-mutant PDAC (RASolute 302- NCT06625320), NSCLC (NCT06881784), and other RAS-mutant solid tumors (NCT05379985). We have therefore considered it a high priority to evaluate the preclinical efficacy of daraxonrasib in models of RAS-driven RMS. Methods and experimental procedures: We used genetic and functional approaches to define drug responses to daraxonrasib in a genomically heterogeneous panel of RMS tumor models including patient-derived cell lines and murine xenografts (PDX) as well as isogenic systems representing the most commonly occurring HRAS, NRAS, and KRAS mutations in FN-RMS. Data: We found that daraxonrasib potently decreased RAS-MEK-ERK signaling and inhibited in vitro growth of FN-RMS cell lines harboring RAS mutations or (WT) RAS lines with RTK activation. Daraxonrasib was significantly less potent in (WT) RAS fusion positive RMS cell lines. In RAS-less mouse embryonic fibroblasts (MEF), or NRAS mutant C2C12 myoblasts, daraxonrasib inhibited ERK1/2 and MEK1/2 phosphorylation more potently compared to NRAS-WT expressing cells. Daraxonrasib led to tumor regression and reduced MEK-ERK signaling in RAS-mutant PDX models, with complete regressions in three models harboring NRAS Q61H, NRAS G13R, or HRAS Q61K mutations. Prolonged exposure to daraxonrasib resulted in adaptive upregulation of HER3 and PI3K-AKT signaling and rebound antitumor activity. High-throughput screens identified that daraxonrasib was synergistic with inhibitors of RAS-MEK-ERK, PI3K-AKT-mTOR, and TEAD pathways, highlighting the potential for a variety of therapeutic combinations. Conclusions: Our data demonstrate that RAS(ON)i decreases RAS-MEK-ERK signaling and inhibits in vitro and in vivo tumor growth in RMS driven by oncogenic RAS signaling. Daraxonrasib may exhibit synergistic potential with inhibition of other cancer cell dependencies, and combination therapy may overcome adaptive RAS-ERK activation. These findings can rapidly translate into trials for patients with RAS-pathway-altered RMS using clinically available compounds in late-stage clinical development. Citation Format: Patience Odeniyide, Sameer U. Khan, Elizabeth Fenner, Katia Campos, Andrew Baker, Hanah Amirkhanian, Craig Thomas, Marielle Yohe, Angelina Vaseva, Christine Pratilas. Pan-RAS Inhibition as a novel therapeutic strategy for RAS-driven rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B046.