Abstract 2602: KRAS G12D and G12V specific alkylating agent (KR12) inhibits growth of colon cancer with those KRAS mutations in vitro as well as in vivo

Abstract Despite extensive efforts to develop chemotherapeutic drug(s) targeting mutated RAS, the successful drug discovery, especially targeting KRAS codon 12 mutation, has never been made. We have found that Pyrrole-Imidazole polyamide seco-CBI conjugate (KR12) selectively recognized mutated KRAS sequence (ACGCCT-A/T-CA) at codon 12 and significantly suppressed tumor growth specifically in human colon cancer cells with G12D or G12V mutation. KRAS expression suppressed preferentially at mutated allele and active KRAS were markedly reduced. G2/M arrest, senescence and subsequent apoptosis by activating the p53 pathway were observed in KR12-exposed LS180 cells with G12D heterozygous mutation. In LS180 and SW480 (G12V homozygous mutation) xenograft colon cancer models, KR12 treatment induced massive tumor growth suppression with low host toxicity. Collectively, our current results strongly suggest that KR12 is a specific alkylating agent against KRAS codon 12 mutations, and could become a powerful candidate compound for the unmet need of KRAS-mutant tumor treatment. Citation Format: Hiroki Nagase, Kiriko Hiraoka, Takahiro Inoue, Takayoshi Watanabe, Ken-Ichi Shinohara, Nobuko Koshikawa, Ozaki Toshinori. KRAS G12D and G12V specific alkylating agent (KR12) inhibits growth of colon cancer with those KRAS mutations in vitro as well as in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2602. doi:10.1158/1538-7445.AM2014-2602