Abstract 3809: Pan-RAS inhibitor RMC-7977 overcomes oncogenic RAS signaling and exerts antileukemic effects in CMML/AML cells

Abstract Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by features of both myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN). Patients with CMML have dismal outcomes partially due to their poor responses to the standard treatment with hypomethylating agents, highlighting a need for new treatments. RAS mutations are detected in roughly 50% of CMML patients and in even higher frequency among patients who progress to acute myeloid leukemia (AML). These mutations contribute to a poor prognosis and are also among the most commonly acquired resistance mutations in AML patients treated with targeted therapies. The current strategy to overcome RAS in myeloid malignancies is to target downstream effectors such as MEK, but these therapies are hindered with short-lived clinical response and resistance emergence. However, recent breakthroughs in the direct inhibition of RAS have renewed enthusiasm for targeting RAS-mutant tumors. Currently, there has been little exploration of the potential efficacy and safety of RAS inhibitors in the context of myeloid malignancies. We hypothesize that the RASmulti(ON) inhibitor RMC-7977, a highly selective inhibitor of the active forms of KRAS, HRAS and NRAS, will be effective against RAS-mutated AML cell lines arising from chronic myeloid neoplasms including CMML. We first characterized the effect of RMC-7977 in various AML cell lines with mutated RAS and wild-type RAS that is activated by alternative mutations. RMC-7977 treatment suppressed proliferation in the low nanomolar range in both RAS-mutated and wild type models. The AML cell lines arising from MDS/CMML were particularly sensitive to the RAS inhibitor, with these cells also displaying increased apoptosis when treated with low nanomolar levels of RMC-7977. Cell signaling experiments revealed that low doses of RMC-7977 significantly decreased phosphorylation of MEK and ERK, as well as ERK transcriptional output. RMC-7977 treatment significantly induced apoptosis and reduced AML blasts from patients with RAS-mutated AML that arose from MDS or MDS/MPN including CMML and prolonged survival as a monotherapy in a RAS mutated secondary AML xenograft model. Additionally, treatment with RMC-7977 showed no effect on the survival and differentiation of healthy hematopoietic stem and progenitor cells taken from human donors, strengthening its potential as an effective therapy in CMML and AML with low toxicity. We have demonstrated that the pan-RAS inhibitor RMC-7977 is highly effective against RAS mutated AML cell lines arising from chronic myeloid neoplasms including CMML while sparing healthy hematopoietic stem and progenitor cells. This work provides the rationale to continue evaluating RAS inhibitors as a targeted therapy in RAS-mutated myeloid malignancies, which is a significant unmet need in the treatment of these conditions. Citation Format: Tessa Seale, Brandy Perkins, Theodora Chatzilygeroudi, Soren Cole, Kareem Battah, Santiago Borrego Garcia, Maximilian Stahl, Mark J. Levis, Alexander Ambinder, Theodoros Karantanos, Sandra Misale. Pan-RAS inhibitor RMC-7977 overcomes oncogenic RAS signaling and exerts antileukemic effects in CMML/AML cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3809.