The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity
The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity
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DOI：
10.1038/s41586-019-1694-1
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发表时间：
2019-11-07
期刊：
影响因子：
64.8
通讯作者：
Lipford, J. Russell
中科院分区：
文献类型：
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作者：
Canon, Jude;Rex, Karen;Lipford, J. Russell
KRAS是癌症中最常突变的癌基因，并编码肿瘤中的关键信号蛋白（1，2）。KRAS（G12 C）突变体具有半胱氨酸残基，其已被用于设计具有有希望的临床前活性的共价抑制剂（3-5）。在这里，我们优化了一系列抑制剂，使用新的结合相互作用，以显着提高其效力和选择性。我们的努力导致了AMG 510的发现，据我们所知，这是临床开发中的第一种KRAS（G12 C）抑制剂。在临床前分析中，AMG 510治疗导致KRAS（G12 C）肿瘤消退，并改善化疗和靶向药物的抗肿瘤疗效。在具有免疫能力的小鼠中，AMG 510治疗导致促炎性肿瘤微环境，并单独以及与免疫检查点抑制剂联合治疗产生持久治愈。治愈的小鼠拒绝了同基因KRAS（G12 D）肿瘤的生长，这表明对共享抗原的适应性免疫。此外，在临床试验中，AMG 510在首次给药队列中表现出抗肿瘤活性，代表了缺乏有效治疗的患者的潜在变革性治疗。
KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours(1,2). The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity(3-5). Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRAS(G12C) tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS(G12D) tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.