(PA-282) Pan-RAS Inhibitor RMC-6236 Suppresses Myeloma Growth and Shows Enhanced Efficacy with SWI/SNF Inhibition

Oncogenic RAS signaling is a central driver of multiple myeloma (MM), with alterations in KRAS, NRAS, or FGFR3 present in nearly half of all cases. The development of tri-complex pan-RAS inhibitors offers a promising strategy to address this critical therapeutic gap in MM.

Methods:   

We evaluated the anti-myeloma activity of novel pan-RAS inhibitors, RMC-6236 and RMC-7977, across a broad panel of over 50 MM cell lines. Drug effects and mechanisms were assessed using viability assay, phosphoproteomics, Western blotting, and proximity ligation assays (PLA). In vivo anti-tumor activity and toxicity were tested using MM xenograft models. High throughput drug combination screens explored synergy effect with several agents targeting cell cycle, mTORC1/2, and SWI/SNF complex.

Results:   

RMC-6236 and RMC-7977 induced potent and selective cytotoxicity in KRAS-, NRAS-, and FGFR3-dependent MM lines, with IC₅₀ values in the low nanomolar range. In vivo, daily oral administration of RMC-6236 (10mg/kg) significantly suppressed tumor growth without observable toxicity. Phosphoproteomic analysis showed decreased phosphorylation of MAPK1/3 and mTORC1 substrates (EIF4EBP1, RPS6KA3, RPS6). Western blots confirmed reduced phosphorylation of MEK (S217/221), S6K (T389), and RPS6 (S235/236), indicating suppression of MAPK and mTORC1 signaling following RMC-6236 treatment. PLA demonstrated that RMC-6236 disrupted interactions between RAS and its downstream effectors MEK, MTOR, and SLC3A2. High throughput combinatorial drug screens discovered that RMC-6236 was highly synergistically toxic in combination with SWI/SNF inhibitor FHD-286. Combined treatment with RMC-6236 and FHD-286 induced potent apoptosis and robust tumor growth suppression in xenograft models.

Conclusions:   

Our findings demonstrate that RMC-6236 shows broad and potent anti-tumor activity in RAS- and FGFR3-driven MM by suppressing MAPK and mTORC1 signaling. Its therapeutic efficacy is significantly enhanced in combination with SWI/SNF inhibitor FHD-286. These findings represent a promising therapeutic strategy that supports further clinical investigation in RAS-dependent MM.