Oncogenic RAS mutant (RASMUT) proteins have been considered undruggable via conventional antibody regimens owing to the intracellular location restricting conventional-antibody accessibility. Here, we report a pan-RAS-targeting IgG antibody, inRas37, which directly targets the intracellularly activated form of various RASMUT subtypes after tumor cell-specific internalization into the cytosol to block the interactions with effector proteins, thereby suppressing the downstream signaling. Systemic administration of inRas37 exerted a potent antitumor activity in a subset of RASMUT tumor xenografts in mice, but little efficacy in RASMUT tumors with concurrent downstream PI3K mutations, which were overcome by combination with a PI3K inhibitor. The YAP1 protein was up-regulated as an adaptive resistance-inducing response to inRas37 in RASMUT-dependent colorectal tumors; accordingly, a combination of inRas37 with a YAP1 inhibitor manifested synergistic antitumor effects in vitro and in vivo. Our study offers a promising pan-RAS-targeting antibody and the corresponding therapeutic strategy against RASMUT tumors.

中文翻译：

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使用肿瘤特异性胞质穿透抗体直接靶向致癌 RAS 突变体可抑制 RAS 突变体驱动的肿瘤生长。

由于细胞内位置限制了常规抗体的可及性，致癌 RAS 突变体 (RASMUT) 蛋白被认为无法通过常规抗体方案进行药物治疗。在这里，我们报道了一种泛RAS靶向IgG抗体inRas37，它在肿瘤细胞特异性内化到细胞质后直接靶向各种RASMUT亚型的细胞内激活形式，以阻断与效应蛋白的相互作用，从而抑制下游信号传导。全身给药 inRas37 在小鼠的一部分 RASMUT 肿瘤异种移植物中发挥了有效的抗肿瘤活性，但对同时存在下游 PI3K 突变的 RASMUT 肿瘤几乎没有作用，通过与 PI3K 抑制剂联合使用可以克服这种作用。在依赖于 RASMUT 的结直肠肿瘤中，YAP1 蛋白作为对 inRas37 的适应性耐药诱导反应而上调；因此，inRas37与YAP1抑制剂的组合在体外和体内表现出协同抗肿瘤作用。我们的研究提供了一种有前景的泛 RAS 靶向抗体以及相应的针对 RASMUT 肿瘤的治疗策略。