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Nat Commun. 2015 Apr 27;6:6706. doi: 10.1038/ncomms7706.

Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate.

Author information

1
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
2
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
3
Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
4
Department of Gastroenterology, Chiba Cancer Center, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
5
Innovative Therapy Research Group, Nihon University Research Institute of Medical Science, Nihon University School of Medicine, 30-1 Ooyaguchi-kami, Itabashi-ku, Tokyo 173-8610, Japan.
6
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA.

Abstract

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.

PMID:
25913614
DOI:
10.1038/ncomms7706
[Indexed for MEDLINE]

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