Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
Nat Commun. 2015 Apr 27;6:6706. doi: 10.1038/ncomms7706.
Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours.
尽管人们已经做出了广泛的努力来针对突变的 RAS 蛋白，但仍然缺乏能够选择性地杀死携带 KRAS 突变的肿瘤细胞的抗癌药物。在这里，我们展示了使用一种合成的烷化剂（吡咯-咪唑聚酰胺吲哚- sec-CBI 缀合物；KR12）来直接靶向 KRAS 突变 DNA，该烷化剂选择性地识别致癌密码子 12 位 KRAS 突变。KR12 在靶序列上使腺嘌呤 N3 烷基化，导致携带 G12D 或 G12V 突变的人结肠癌细胞中的链断裂和生长抑制，从而诱导衰老和凋亡。在异种移植模型中，KR12 输注可显著抑制肿瘤生长，而在 KRAS 突变型而非野生型肿瘤中，宿主毒性较低。这种新开发的方法可能适用于靶向人类肿瘤中的其他突变驱动致癌基因。
