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- transcription and cancer cell proliferation . 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-RAS 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.

中文翻译：

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肌管蛋白相关蛋白 7 通过直接相互作用抑制突变体 (G12V) K-RAS

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 信号传导的重新激活产生的治疗耐药性。我们假设肌管蛋白相关蛋白 7 (MTMR7) 可抑制 RAS 下游的 PI3K 和 ERK1/2 信号传导，直接靶向 RAS，从而防止耐药性。通过细胞和结构生物学与动物研究相结合，我们发现 MTMR7 在细胞膜上结合并抑制 RAS。 MTMR7 的过度表达降低了 RAS GTPase 活性和蛋白水平、ERK1/2 磷酸化、c 转录和癌细胞增殖。我们将 MTMR7 的 RAS 抑制活性定位于其带电卷曲线圈 (CC) 区域，并证明与胃肠道癌相关的 K-RAS 突变体直接相互作用，有利于其 GDP 结合状态。在胃癌和肠癌小鼠模型中，细胞渗透性 MTMR7-CC 拟态肽可降低肿瘤生长、Ki67 增殖指数和 ERK1/2 核阳性。因此，MTMR7 模拟肽可以提供一种针对癌症中突变 K-RAS 的新策略。