Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate.
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.
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Kiriko
K
Hiraoka
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Takahiro
T
Inoue
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
Rhys Dylan
RD
Taylor
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Takayoshi
T
Watanabe
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Nobuko
N
Koshikawa
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Hiroyuki
H
Yoda
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Ken-ichi
K
Shinohara
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Atsushi
A
Takatori
Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Hirokazu
H
Sugimoto
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Yoshiaki
Y
Maru
Department of Gastroenterology, Chiba Cancer Center, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Tadamichi
T
Denda
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.
Kyoko
K
Fujiwara
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA.
Allan
A
Balmain
Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Toshinori
T
Ozaki
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
Toshikazu
T
Bando
Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
Hiroshi
H
Sugiyama
Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Hiroki
H
Nagase
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage; D004353:Drug Evaluation, Preclinical; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D008819:Mice, Nude; D009154:Mutation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009757:Nylons / Q000138:chemical synthesis* / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D007093:Imidazoles; C000605800:KR12 compound; C117307:KRAS protein, human; D009757:Nylons; D016283:Proto-Oncogene Proteins p21(ras)