小柯机器人

美国纪念斯隆-凯特琳癌症中心Piro Lito团队揭示与KRAS(G12C)抑制的耐药相关的多样化改变。相关论文于2021年11月10日在线发表在《自然》杂志上。

研究人员评估了43名接受KRAS(G12C)抑制剂sotorasib治疗的患者治疗前和治疗后的匹配标本。在27名患者中观察到多种治疗引起的改变，包括KRAS、NRAS、BRAF、EGFR、FGFR2、MYC和其他基因的改变。在临床前患者衍生的异种移植和细胞系模型中，对KRAS(G12C)抑制的耐药性与KRAS(G12V或G13D)、NRAS(Q61K或G13R)、MRAS(Q71R)和/或BRAF(G596R)的低等位基因频率热点突变有关。等位基因谱系的单细胞测序确定了与KRAS(G12C)相同细胞中的次级RAS和/或BRAF突变，它们绕过了抑制而不影响靶点失活。遗传或药物靶向ERK信号中间物增强了G12C抑制剂在获得性RAS或BRAF突变的模型中的抗增殖作用。

因此，这项研究表明，在G12C抑制剂治疗过程中出现了多种亚克隆事件，是一种异质性的耐药模式。这个队列中的一部分患者获得了致癌性KRAS、NRAS或BRAF突变，这种情况下的耐药性可能通过联合靶向ERK信号中间物而被延迟。这些发现值得在前瞻性的临床试验中进行更广泛的评估。

据介绍，失活状态的选择性KRAS(G12C)抑制剂显示出30-40%的反应率，并使肺癌患者的中位无进展生存期达到约6个月。对这些第一类突变体GTP酶抑制剂产生耐药性的遗传基础仍在调查之中。

附：英文原文

Title: Diverse alterations associated with resistance to KRAS(G12C) inhibition

Author: Zhao, Yulei, Murciano-Goroff, Yonina R., Xue, Jenny Y., Ang, Agnes, Lucas, Jessica, Mai, Trang T., Da Cruz Paula, Arnaud F., Saiki, Anne Y., Mohn, Deanna, Achanta, Pragathi, Sisk, Ann E., Arora, Kanika S., Roy, Rohan S., Kim, Dongsung, Li, Chuanchuan, Lim, Lee P., Li, Mark, Bahr, Amber, Loomis, Brian R., de Stanchina, Elisa, Reis-Filho, Jorge S., Weigelt, Britta, Berger, Michael, Riely, Gregory, Arbour, Kathryn C., Lipford, J. Russell, Li, Bob T., Lito, Piro

Issue&Volume: 2021-11-10

Abstract: Inactive state-selective KRAS(G12C) inhibitors1,2,3,4,5,6,7,8 demonstrate a 30–40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.

DOI: 10.1038/s41586-021-04065-2

Source: https://www.nature.com/articles/s41586-021-04065-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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