(P 405) PAN-RAS INHIBITION AS A NOVEL THERAPEUTIC STRATEGY FOR RAS-DRIVEN RHABDOMYOSARCOMA

Objective: Attempts to indirectly inhibit RAS and RAS-effector signaling have been unsuccessful in RAS-driven rhabdomyosarcoma. RMC-6236 and its tool compound RMC-7977 are novel state selective pan-RAS inhibitors that inhibit GTP-bound oncogenic and wild-type (WT) RAS, known as RAS(ON)i. RMC-6236 may prevent therapeutic resistance caused by activation of RTK-driven WT-RAS signaling and activation of bypass survival pathways such as PI3K-AKT. RMC-6236 has been active 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 RAS(ON)i in RAS-driven RMS tumor models.

Methods: We used genetic and functional approaches to define drug responses 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.

Results: We found that RAS(ON)i decreased RAS-MEK-ERK signaling, prevented adaptive PI3K-AKT signaling, and decreased in vitro growth in RAS mutant and WT cell lines with RTK activation. 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 promoted myogenic differentiation, as measured by expression of the myogenic transcription factor MYOG in vitro and in vivo.

Conclusion: Our data demonstrate that RAS(ON)i decreases RAS-MEK-ERK signaling, prevents adaptive PI3K-AKT signaling, and decreases in vitro and in vivo tumor growth in RAS-driven RMS. These findings can rapidly translate into a clinical trial for patients with RAS-pathway-altered RMS using clinically available compounds in late-stage clinical development.