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UMIN000001396.

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.

BACKGROUND: OncoBEAM TM RAS CRC kit using BEAMing technology is a circulating tumour DNA (ctDNA) test for detecting plasma RAS mutational status in metastatic colorectal cancer (mCRC). We conducted a multicentre, prospective study to investigate the concordance of the RAS mutational status between plasma ctDNA and tumour tissue DNA. METHODS: mCRC patients without prior anti-EGFR antibodies or regorafenib treatment were enroled. Plasma-and tissue-based RAS mutational status were determined by BEAMing, respectively. RESULTS: A total of 280 patients from eight institutions were eligible. The overall agreement between plasma-and tissue-based analyses was 86.4%, with a positive percent agreement of 82.1% and negative percent agreement of 90.4%. From logistic regression analysis, lung metastasis alone indicated the most significant factor associated with discordance. The agreement between plasma-and tissue-based analyses was 64.5% in patients with lung metastasis alone (n = 31) indicating lower amount of ctDNA. Among the cases with lung metastasis alone, all plasma-and tissue-based analyses were perfectly concordant in cases with ≥20 mm of maximum lesion diameter or ≥10 lesions. CONCLUSION: The clinical validity of OncoBEAM TM RAS CRC kit was confirmed. Careful attention should be paid for mCRC patients with lung metastases alone having fewer metastases or smaller diameter lesions.