Abstract A067: Pan-RAS inhibition as a novel therapeutic strategy in RAS-driven rhabdomyosarcoma

Abstract Attempts to indirectly inhibit RAS and RAS-effector signaling have been unsuccessful in RAS-driven rhabdomyosarcoma (RMS). RMC-6236 (and the related tool compound RMC-7977) are novel state-selective pan-RAS inhibitors that inhibit both GTP-bound oncogenic and wild-type (WT) RAS, known as RAS(ON)i. RMC-6236 may prevent therapeutic resistance caused by the activation of RTK-driven WT-RAS signaling and the activation of bypass survival pathways, such as PI3K-AKT. RMC-6236 has been active in RAS-mutant PDAC, NSCLC, and other RAS-mutant solid tumors. We have therefore considered it a high priority to evaluate the preclinical efficacy of RAS(ON)i in RAS-driven RMS tumor models. We used genetic and functional approaches to define signaling inhibition and antiproliferative activity to RAS(ON)i in a genomically heterogeneous panel of RMS tumor models, including patient-derived cell lines and xenografts (PDX) as well as isogenic systems representing the most commonly occurring HRAS, NRAS, and KRAS mutations. We found that RAS(ON)i decreased RAS-MEK-ERK signaling and decreased in vitro growth in both RAS mutant and WT RAS/ RTK-activated cell lines. RAS(ON)i led to tumor regression and reduced MEK-ERK signaling in RAS-mutant xenograft models. In RAS-driven FN-RMS, hyperactive ERK signaling promotes cell cycling and impairs myogenic differentiation. We found that RAS(ON)i effectively reverses this phenotype, promoting myogenic differentiation, as measured by expression of the transcription factor MYOG. Long-term drug exposure in a mouse model resulted in increased PI3K-AKT signaling in tumors sensitive to RAS(ON)i. Accordingly, we found synergism between pan-RAS and PI3K-AKT inhibitors in vitro. Our data demonstrate that RAS(ON)i decreases RAS-MEK-ERK signaling and decreases in vitro and in vivo tumor growth in RAS-driven RMS. The efficacy of RAS(ON)i is enhanced with concurrent PI3K-AKT inhibition. These findings have the potential to rapidly translate into a clinical trial for patients with RAS-pathway-addicted RMS using clinically available compounds in late-stage clinical development. Citation Format: Patience Odeniyide, Elizabeth Fenner, Andrew Baker, Hanah Amirkhanian, Angelina Vaseva, Craig Thomas, Marielle Yohe, Christine Pratilas. Pan-RAS inhibition as a novel therapeutic strategy in RAS-driven rhabdomyosarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A067.