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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Kiriko Hiraoka & Takahiro Inoue & Rhys Dylan Taylor & Takayoshi Watanabe & Nobuko Koshikawa & Hiroyuki Yoda & Ken-ichi Shinohara & Atsushi Takatori & Hirokazu Sugimoto & Yoshiaki Maru & Tadamichi Dend, 2015. "Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate," Nature Communications, Nature, vol. 6(1), pages 1-8, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7706
    DOI: 10.1038/ncomms7706
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    Cited by:

    1. Jason Lin & Sakthisri Krishnamurthy & Hiroyuki Yoda & Yoshinao Shinozaki & Takayoshi Watanabe & Nobuko Koshikawa & Atsushi Takatori & Paul Horton & Hiroki Nagase, 2019. "Estimating genome-wide off-target effects for pyrrole-imidazole polyamide binding by a pathway-based expression profiling approach," PLOS ONE, Public Library of Science, vol. 14(4), pages 1-15, April.

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