演題抄録

FACO International Workshop

開催概要
開催回
第53回・2015年・京都
 

Inhibition of KRAS mutant colon cancer using a novel DNA-alkylating pyrrole-Imidazole polyamide conjugate targeting KRAS Codon 12 mutant DNA

演題番号 : FWS3-2

[筆頭演者]
Nagase Hiroki:1 
[共同演者]
Hiraoka Kiriko:1、Inoue Takahiro:1、Watanabe Takayoshi:1、Takatori Atsushi:1、Koshikawa Nobuko:1

1:Cancer Genetics, Chiba Cancer Center Research Institute

 

Recent advances in next generation sequencing of human tumors have uncovered hundreds of recurrent oncogenic driver mutations, identifying many novel actionable therapeutic targets. Oncogenic driver genes are continuously expressed, often mutated and thereby contribute to cancer cell survival, which is a target for clinical therapy. Targeting the RAS-MAPK pathway has led to development of successful treatments of EGFR-mutant cancers, but also revealed that there exist unexpected degrees of oncogene addiction and signaling. A common outcome of treatment with these inhibitors of genes that lie "downstream" in the RAS pathway is development of drug resistance, and new approaches that target mutant RAS genes directly may provide a more direct route to inhibition of these aggressive tumors. We semi-automatically synthesized a Pyrrole-Imidazole polyamide conjugate (KR12) which specifically alkylated KRAS codon 12 mutant (G12D or G12V) DNA and induced specific suppression of KRAS mutant allele. KR12 induced cellular senescence followed by p53-dependent apoptosis preferentially in KRAS (G12D or G12V) mutated cell lines, but not in cells with wild type KRAS or other type of mutations. KR12 displayed a significant anti-tumor effect of human colorectal cancer xenografts harboring KRAS codon 12 mutations with minimum host toxicity. Although KR12 is still under development for clinical trial, this sequence-dependent alkylating approach may open a new strategy not only for mutated KRAS but also for future 'precise medicine'.

キーワード

臓器別:大腸・小腸

手法別:トランスレーショナルリサーチ

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