KRAS（G12C）突變的耐藥機制
作者：
小柯機器人發布時間：2020/1/10 13:56:53
美國紀念斯隆-凱特琳癌症中心Piro Lito研究團隊發現，對構象特異性KRAS（G12C）抑制的快速非均勻適應。這一研究成果於2020年1月8日在線發表於國際學術期刊《自然》。
由於KRAS（G12C）在活性和非活性構象之間循環，並且抑制劑僅與後者結合，因此研究人員通過研究單細胞解析度下的治療效果來測試了同基因細胞群體是否以非均勻的方式反應。研究人員發現，在治療後不久，一些癌細胞被變為靜止狀態，並具有較低的KRAS活性，而另一些則繞過這種作用以恢復增殖。之所以會出現這種快速的差異反應，是因為某些靜止細胞響應抑制的MAPK（mitogen-activated protein kinase）信號而產生新的KRAS（G12C）。新的KRAS（G12C）通過表皮生長因子受體和aurora激酶信號轉導保持在活躍、藥物不敏感的狀態。沒有這些適應性改變的細胞或在藥理學上抑制了這些改變的細胞仍然對藥物治療敏感，因為新的KRAS（G12C）要麼不存在，要麼以非活性藥物敏感性狀態存在。直接靶向KRAS癌蛋白一直是精準腫瘤研究的長期目標。這項研究發現了一種靈活的非均勻適應性機制，其可使群體中的細胞群迅速繞過治療效果。如果想要在臨床獲得完整和持久的響應，就必須克服這種適應性過程。
研究人員表示，KRAS GTP酶在三分之一的癌症中被激活，而KRAS（G12C）是肺腺癌中最常見的激活改變之一。KRAS（G12C）抑制劑正在進行I期臨床試驗，早期數據顯示近一半的肺癌患者有部分緩解。癌細胞如何繞過抑制作用從而防止對治療產生最大反應尚不清楚。
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