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美国纪念斯隆-凯特琳癌症中心Piro Lito研究团队发现，对构象特异性KRAS（G12C）抑制的快速非均匀适应。这一研究成果于2020年1月8日在线发表于国际学术期刊《自然》。

研究人员表示，KRAS GTP酶在三分之一的癌症中被激活，而KRAS（G12C）是肺腺癌中最常见的激活改变之一。KRAS（G12C）抑制剂正在进行I期临床试验，早期数据显示近一半的肺癌患者有部分缓解。癌细胞如何绕过抑制作用从而防止对治疗产生最大反应尚不清楚。

附：英文原文

Title: Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition

Author: Jenny Y. Xue, Yulei Zhao, Jordan Aronowitz, Trang T. Mai, Alberto Vides, Besnik Qeriqi, Dongsung Kim, Chuanchuan Li, Elisa de Stanchina, Linas Mazutis, Davide Risso, Piro Lito

Issue&Volume: 2020-01-08

Abstract: KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma1,2. KRAS(G12C) inhibitors3,4 are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation46, and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changesor cells in which these changes are pharmacologically inhibitedremain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic. Populations of KRAS(G12C)-mutant cancer cells can rapidly bypass the effects of treatment with KRAS(G12C) inhibitors because a subset of cells escapes drug-induced quiescence by producing new KRAS(G12C) that is maintained in its active, drug-insensitive state.

DOI: 10.1038/s41586-019-1884-x

Source:https://www.nature.com/articles/s41586-019-1884-x

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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