小柯机器人

美国哈佛医学院Pasi A. Jänne、Yoshihisa Kobayashi等研究人员合作揭示RAS Q61肿瘤中的的治疗靶点。相关论文于2022年3月2日在线发表在《自然》杂志上。

研究人员表示，RAS家族成员是人类癌症中最经常突变的致癌基因。尽管KRAS(G12C)特异性抑制剂在癌症患者中显示出临床活性，但目前还没有NRAS、HRAS或非G12C KRAS变体的直接抑制剂。

研究人员揭示了沉默的KRAS^G60G突变对细胞产生功能性KRAS(Q61K)的要求。在KRAS^Q61K中没有这个G60G突变时，会形成一个隐性剪接供体位点，促进替代剪接和蛋白质过早终止。G60G沉默突变消除了剪接供体位点，产生了一个功能性的KRAS(Q61K)变体。研究人员在三个独立的泛癌症队列中检测到了KRAS^Q61K和G60G/A59A沉默突变的一致情况。RAS Q61周围的区域富含外显子剪接增强子（ESE）模体，研究人员设计了突变体特异性寡核苷酸来干扰ESE介导的剪接，以突变体选择性的方式使RAS(Q61)蛋白失去功能。反义寡核苷酸对异常剪接的诱导在体外和体内表现出治疗效果。

通过研究功能性KRAS(Q61K)所需的剪接，研究人员发现了一种针对RAS^Q61癌症的突变体选择性治疗策略，并揭示了一种突变体的特异性弱点，这有可能被用于其他遗传背景下的治疗。

附：英文原文

Title: Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers

Author: Kobayashi, Yoshihisa, Chhoeu, Chhayheng, Li, Jiaqi, Price, Kristin S., Kiedrowski, Lesli A., Hutchins, Jamie L., Hardin, Aaron I., Wei, Zihan, Hong, Fangxin, Bahcall, Magda, Gokhale, Prafulla C., Jnne, Pasi A.

Issue&Volume: 2022-03-02

Abstract: RAS family members are the most frequently mutated oncogenes in human cancers. Although KRAS(G12C)-specific inhibitors show clinical activity in patients with cancer1–3, there are no direct inhibitors of NRAS, HRAS or non-G12C KRAS variants. Here we uncover the requirement of the silent KRASG60G mutation for cells to produce a functional KRAS(Q61K). In the absence of this G60G mutation in KRASQ61K, a cryptic splice donor site is formed, promoting alternative splicing and premature protein termination. A G60G silent mutation eliminates the splice donor site, yielding a functional KRAS(Q61K) variant. We detected a concordance of KRASQ61K and a G60G/A59A silent mutation in three independent pan-cancer cohorts. The region around RAS Q61 is enriched in exonic splicing enhancer (ESE) motifs and we designed mutant-specific oligonucleotides to interfere with ESE-mediated splicing, rendering the RAS(Q61) protein non-functional in a mutant-selective manner. The induction of aberrant splicing by antisense oligonucleotides demonstrated therapeutic effects in vitro and in vivo. By studying the splicing necessary for a functional KRAS(Q61K), we uncover a mutant-selective treatment strategy for RASQ61 cancer and expose a mutant-specific vulnerability, which could potentially be exploited for therapy in other genetic contexts. A translationally silent KRASG60G mutation, preventing the formation of a cryptic splice donor site and  enabling expression of KRAS(Q61K), reveals a vulnerability in RASQ61 cancers that are therapeutically exploitable in a mutant-selective manner.

DOI: 10.1038/s41586-022-04451-4

Source: https://www.nature.com/articles/s41586-022-04451-4

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