KRAS Q61H Mutation Confers Cancer Cells with Acquired Resistance to SHP2 Inhibition

Yi-Hui Song, Xin-yu Yang, Bin Yu
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引用次数: 1

Abstract

Cancer cells with varied KRAS mutations exhibit different sensitivity to SHP2 inhibition. A recent work published in Nature Communications revealed the underlying drug resistance mechanism of cancer cells harboring KRAS Q61H mutation to SHP2 inhibitors (SHP2i). 1 This work showed that KRAS Q61H mutation renders cancer cells resistant to SHP2i via decoupling KRAS from SHP2-mediated upstream nucleotide exchange factors for (guanine nucleotide exchange factor [GEF])/GTPase activating protein (GAP) regulation, providing newinsightsintotreatingcancerswithKRASQ61Hmutations. KRAS, the most frequently mutated RASisoform, isa proto-oncogene that encodes small GTPase transductor protein. In response to upstream signals, KRAS can switch between inactive guanosine diphosphate (GDP) state and active guano-sinetriphosphate (GTP) stateby GEFs, such as Sonof Sevenless (SOS),orGAPs. 2 KRASmutations,primarilyatcodons12,13,or 61, account for 86% of RAS mutations. In particular, glutamine
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KRAS Q61H突变赋予癌细胞对SHP2抑制的获得性抗性
不同KRAS突变的癌细胞对SHP2抑制表现出不同的敏感性。最近发表在《自然通讯》上的一项研究揭示了含有KRAS Q61H突变的癌细胞对SHP2抑制剂(SHP2i)的潜在耐药机制。这项研究表明,KRASQ61H突变通过将KRAS与shp2介导的上游核苷酸交换因子(鸟嘌呤核苷酸交换因子[GEF])/GTPase激活蛋白(GAP)调控解耦,使癌细胞对SHP2i产生抗性,为krasq61h突变治疗癌症提供了新的视角。KRAS是最常发生突变的RASisoform,是一种原癌基因,编码小的GTPase转导蛋白。KRAS响应上游信号,可以通过全球环境基金(如Sonof Sevenless (SOS)、orgap)在非活性鸟苷二磷酸(GDP)状态和活性鸟苷三磷酸(GTP)状态之间切换。2个kras突变,主要发生在12、13或61号密码子上,占RAS突变的86%。尤其是谷氨酰胺
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审稿时长
15 weeks
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