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伴侣指导的异构功能分子绕过了KRAS^G12C抑制剂的耐药性

Ines Pulido¹, Qiyue Luan², Sara Pastor-Puente³

¹Department of Surgery, Division of Cardiothoracic Surgery, University of Illinois Chicago, Chicago, IL, 60612, USA; University of Illinois Hospital & Health Sciences System Cancer Center, University of Illinois Chicago, Chicago, IL, 60612, USA.

|April 9, 2025

概括

新药RNK07421针对KRAS G12C和HSP90蛋白质,以克服KRAS G12C驱动的癌症中获得的耐药性. 这种双重抑制策略显示出对患者更持久的反应有希望.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

克拉斯G12C抑制剂显示临床活性,但获得的耐药性限制了持久的反应.
对KRAS G12C抑制剂的组合疗法面临毒性和剂量挑战.
对阿达格拉西布的获得性耐药性涉及HSP90客户端蛋白的丰富,表明了脆弱性.

研究的目的:

开发一种针对KRAS G12C和HSP90的新型治疗策略,以克服获得的耐药性.
在KRAS G12C驱动癌症的临床前模型中评估双重抑制剂RNK07421的疗效.

主要方法:

开发了RNK07421,一种向KRAS G12C和HSP90客户端coproteins的异构生物功能分子.
利用结构和生化分析来了解RNK07421的作用机制.
在KRAS G12C突变细胞系中评估了体外疗效,并在异种移植模型中评估了体内疗效.

主要成果:

RNK07421通过诱导与HSP90的非自然接口来破坏KRAS G12C相互作用,从而损害瘤信号传输.
在耐药的KRAS G12C细胞系中,RNK07421抑制了ERK的活性和降低了活力.
在体内,RNK07421显著降低了瘤负担,超过单一疗法和组合疗法.

结论:

双重KRAS G12C和HSP90抑制是克服KRAS G12C驱动癌症抵抗力的有希望的策略.
RNK07421表现出强大的抗瘤活性,克服了抵抗机制.
这种方法为KRAS G12C突变癌症患者的持久反应提供了潜在的新途径.

关键词:

在G12C中,G12C是指G12C 在HSP90中,它是HSP90的.克拉斯 (Kras) 是一个国家.在NSCLCLC中,我们可以看到.电阻电阻电阻电阻电阻电阻

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