Abstract：
Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes. Overexpression of MTMR7 reduced RAS GTPase activities and protein levels, ERK1/2 phosphorylation, c-FOS transcription and cancer cell proliferation in vitro. We located the RAS-inhibitory activity of MTMR7 to its charged coiled coil (CC) region and demonstrate direct interaction with the gastrointestinal cancer-relevant K-RASG12V mutant, favouring its GDP-bound state. In mouse models of gastric and intestinal cancer, a cell-permeable MTMR7-CC mimicry peptide decreased tumour growth, Ki67 proliferation index and ERK1/2 nuclear positivity. Thus, MTMR7 mimicry peptide(s) could provide a novel strategy for targeting mutant K-RAS in cancers.
摘要：
K-RAS效应子(如B-RAF或MEK1/2)的抑制伴随着癌症患者通过PI3K和Wnt信号的再激活的治疗抗性。我们假设肌管蛋白相关蛋白7(MTMR7)，抑制RAS下游的PI3K和ERK1/2信号传导，直接针对RAS，从而防止阻力。利用细胞和结构生物学结合动物研究，我们显示MTMR7结合并抑制细胞膜上的RAS.MTMR7的过表达降低了RASGTPase活性和蛋白质水平，ERK1/2磷酸化，c-FOS转录与体外癌细胞增殖。我们将MTMR7的RAS抑制活性定位到其带电的卷曲螺旋（CC）区域，并证明了与胃肠道癌症相关的K-RASG12V突变体的直接相互作用，有利于其GDP约束状态。在胃癌和肠癌的小鼠模型中，细胞通透性MTMR7-CC模拟肽降低肿瘤生长，Ki67增殖指数和ERK1/2核阳性。因此，MTMR7模拟肽可以提供用于在癌症中靶向突变K-RAS的新策略。
