Multi-selective RAS(ON) Inhibition Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 and BCL2 Inhibitors in Acute Myeloid Leukemia

Aberrant activation of the RAS/MAPK signaling limits the clinical efficacy of several targeted therapies in acute myeloid leukemia (AML). In FLT3-mutant AML, the selection of clones harboring heterogeneous RAS mutations drives resistance to FLT3 inhibitors (FLT3i). RAS activation is also associated with resistance to other AML targeted therapies, including the BCL2 inhibitor venetoclax. Despite the critical need to inhibit RAS/MAPK signaling in AML, no targeted therapies have demonstrated clinical benefit in RAS-driven AML. To address this unmet need, we investigated the preclinical activity of RMC-7977, a multi-selective inhibitor of GTP-bound active [RAS(ON)] isoforms of mutant and wild-type RAS in AML models. RMC-7977 exhibited potent antiproliferative and pro-apoptotic activity across AML cell lines with MAPK-activating signaling mutations. In Molm-14 and OCIAML-3 cell lines, RMC=7977 downregulated expression of genesets involved in RAS/MAPK and PI3K/Akt/mTOR signaling, as well as MYC targets and cell cycle regulators. Overall design: AML cell lines Molm-14 and OCIAML-3 were treated for 2h and 24 hours with either DMSO or the RAS(ON) inhibitor RMC-7977, then RNA was isolated and RNA sequencing was performed.

RAS/MAPK信号通路的异常激活会限制急性髓系白血病（acute myeloid leukemia，AML）中多种靶向治疗的临床疗效。在携带FLT3突变的AML中，携带异质性RAS突变的克隆的筛选会导致对FLT3抑制剂（FLT3 inhibitors，FLT3i）的耐药性。RAS激活还与AML其他靶向治疗的耐药性相关，包括BCL2抑制剂维奈克拉（venetoclax）。尽管AML中亟需抑制RAS/MAPK信号通路，但目前尚无靶向疗法在RAS驱动型AML中展现出临床获益。为解决这一未被满足的临床需求，我们在AML模型中探究了RMC-7977的临床前活性——RMC-7977是一种多选择性抑制剂，可靶向突变型及野生型RAS的GTP结合活化型[RAS(ON)]亚型。RMC-7977在携带MAPK激活信号突变的AML细胞系中展现出强效的抗增殖与促凋亡活性。在Molm-14与OCIAML-3细胞系中，RMC-7977下调了参与RAS/MAPK及PI3K/Akt/mTOR信号通路、MYC靶点以及细胞周期调控因子的基因集的表达。实验整体设计：将AML细胞系Molm-14与OCIAML-3分别用二甲基亚砜（dimethyl sulfoxide，DMSO）或RAS(ON)抑制剂RMC-7977处理2小时与24小时，随后提取RNA并进行RNA测序（RNA sequencing）。