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^4,5,6, 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.

KRAS GTP 酶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正在进行 I 期临床试验，早期数据显示近一半肺癌患者有部分缓解。癌细胞如何绕过抑制来阻止对治疗的最大反应尚不清楚。由于 KRAS(G12C) 在活性和非活性构象之间循环^4,5,6 ，并且抑制剂仅与后者结合，因此我们通过研究单次治疗的效果来测试同基因细胞群是否以不均匀的方式做出反应。细胞分辨率。在这里，我们报告说，治疗后不久，一些癌细胞被隔离在 KRAS 活性较低的静止状态，而其他癌细胞则绕过这种效应恢复增殖。这种快速发散反应的发生是因为一些静止细胞响应受抑制的丝裂原激活蛋白激酶输出而产生新的 KRAS(G12C)。新 KRAS(G12C) 通过表皮生长因子受体和极光激酶信号传导维持在其活性、药物不敏感状态。没有这些适应性变化的细胞，或者这些变化在药理上受到抑制的细胞，仍然对药物治疗敏感，因为新的 KRAS(G12C) 要么不可用，要么以其非活性、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机制，使群体内的细胞群能够快速绕过治疗的效果。如果我们要在临床上实现完全且持久的反应，就必须克服这种适应性过程。