Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition.
Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition.
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KRAS G12C抑制的快速特异性临床耐药机制
DOI：
10.1172/jci155523
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发表时间：
2022-02-15
期刊：
影响因子：
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通讯作者：
Pecot CV
中科院分区：
文献类型：
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作者：
Tsai YS;Woodcock MG;Azam SH;Thorne LB;Kanchi KL;Parker JS;Vincent BG;Pecot CV
KRAS原癌基因是癌症中最常见的突变基因之一，但40年来它仍然是一个难以捉摸的治疗靶点。最近，共价结合KRAS G12 C突变的变构抑制剂已被批准用于肺腺癌。虽然观察到了反应，但它们往往是短暂的，因此深入表征耐药机制至关重要。在这里，我们提出了一个快速尸检的情况下，病人谁KRASG 12 C突变肺腺癌谁最初响应KRAS G12 C抑制剂，但随后迅速发展耐药。使用deep-RNA和全外显子组测序比较治疗前，治疗后和匹配的正常组织，我们发现了对直接KRAS抑制的抗性的许多机制。除了难治性肿瘤中KRAS G12 C突变等位基因频率降低外，我们还发现MAPK通路的重新激活，尽管KRAS或其下游介质中没有新的突变。肿瘤细胞内在和非细胞自主机制包括补体激活、凝血和肿瘤血管生成增加，以及免疫逃避的几条证据。总之，我们的研究结果揭示了通过克隆群体的富集，KRAS独立的下游信号传导和肿瘤微环境的多样化重塑对当前KRAS G12 C抑制剂的耐药性的多种机制。理查德和弗兰·杜利，吉米和凯曼，国家卫生研究院，以及北卡罗来纳州生物技术中心。
The KRAS proto-oncogene is among the most frequently mutated genes in cancer, yet for 40 years it remained an elusive therapeutic target. Recently, allosteric inhibitors that covalently bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. Although responses are observed, they are often short-lived, thus making in-depth characterization of the mechanisms of resistance of paramount importance. Here, we present a rapid-autopsy case of a patient who had a KRASG12C-mutant lung adenocarcinoma who initially responded to a KRAS G12C inhibitor but then rapidly developed resistance. Using deep-RNA and whole-exome sequencing comparing pretreatment, posttreatment, and matched normal tissues, we uncover numerous mechanisms of resistance to direct KRAS inhibition. In addition to decreased KRAS G12C–mutant allele frequency in refractory tumors, we also found reactivation of the MAPK pathway despite no new mutations in KRAS or its downstream mediators. Tumor cell–intrinsic and non–cell autonomous mechanisms included increased complement activation, coagulation, and tumor angiogenesis, and several lines of evidence of immunologic evasion. Together, our findings reveal numerous mechanisms of resistance to current KRAS G12C inhibitors through enrichment of clonal populations, KRAS-independent downstream signaling, and diverse remodeling of the tumor microenvironment. Richard and Fran Duley, Jimmy and Kay Mann, the NIH, and the North Carolina Biotechnology Center.