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

Kiriko Hiraoka, Takahiro Inoue, Rhys Dylan Taylor, Takayoshi Watanabe, Nobuko Koshikawa, Hiroyuki Yoda, Ken-ichi Shinohara, Atsushi Takatori, Hirokazu Sugimoto, Yoshiaki Maru, Tadamichi Denda, Kyoko Fujiwara, Allan Balmain, Toshinori Ozaki, Toshikazu Bando, Hiroshi Sugiyama and Hiroki Nagase ()
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Kiriko Hiraoka: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute
Takahiro Inoue: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute
Rhys Dylan Taylor: Graduate School of Science, Kyoto University
Takayoshi Watanabe: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute
Nobuko Koshikawa: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute
Hiroyuki Yoda: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute
Ken-ichi Shinohara: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute
Atsushi Takatori: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute
Hirokazu Sugimoto: Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute
Yoshiaki Maru: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute
Tadamichi Denda: Chiba Cancer Center
Kyoko Fujiwara: Innovative Therapy Research Group, Nihon University Research Institute of Medical Science, Nihon University School of Medicine
Allan Balmain: Helen Diller Family Comprehensive Cancer Center, University of California
Toshinori Ozaki: Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute
Toshikazu Bando: Graduate School of Science, Kyoto University
Hiroshi Sugiyama: Graduate School of Science, Kyoto University
Hiroki Nagase: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7706

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