Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition
Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition
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DOI：
10.1038/s41586-019-1884-x
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发表时间：
2020-01-08
期刊：
影响因子：
64.8
通讯作者：
Lito, Piro
中科院分区：
文献类型：
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作者：
Xue, Jenny Y.;Zhao, Yulei;Lito, Piro
KRAS gtpase在三分之一的癌症中被激活，KRAS（G12C）是肺腺癌中最常见的激活改变之一（1,2）。KRAS（G12C）抑制剂（3,4）正在i期临床试验中，早期数据显示近一半的肺癌患者部分缓解。癌细胞如何绕过抑制以防止对治疗产生最大反应尚不清楚。由于KRAS（G12C）在活性构象和非活性构象之间循环（4-6），而抑制剂仅与后者结合，我们通过研究单细胞分辨率的处理效果来测试等基因细胞群是否以不均匀的方式反应。在这里，我们报道，在治疗后不久，一些癌细胞被隔离在低KRAS活性的静止状态，而另一些则绕过这种影响恢复增殖。这种快速分化反应的发生是因为一些静止细胞产生新的KRAS(G12C)，以响应抑制丝裂原激活的蛋白激酶输出。新KRAS（G12C）通过表皮生长因子受体和极光激酶信号传导维持其活性，药物不敏感状态。没有这些适应性变化的细胞——或者这些变化受到药理学抑制的细胞——对药物治疗仍然敏感，因为新的KRAS（G12C）要么不可用，要么以不活跃的药物敏感状态存在。直接靶向KRAS癌蛋白一直是精准肿瘤学的长期目标。我们的研究揭示了一种灵活的非均匀适应度机制，使群体内的细胞群能够迅速绕过治疗的影响。如果我们要在临床中获得完整和持久的反应，就必须克服这种适应过程。KRAS（G12C）突变的癌细胞群体可以迅速绕过KRAS（G12C）抑制剂治疗的影响，因为一部分细胞通过产生新的KRAS（G12C）来逃避药物诱导的静止，而新的KRAS（G12C）保持在活跃的、药物不敏感的状态。
KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma(1,2). KRAS(G12C) inhibitors(3,4) 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 conformation(4-6), 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 changes-or cells in which these changes are pharmacologically inhibited-remain 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.