Journal
ONCOTARGET
Volume 8, Issue 32, Pages 53017-53027Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.18078
Keywords
colorectal cancer; trifluridine; 5-fluorouracil; let-7d-5p; drug resistance
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology
- Ministry of Health, Labor, and Welfare
- Taiho Pharmaceutical Co., Ltd.
- Grants-in-Aid for Scientific Research [16K15615, 16K15616, 17K19698, 17H04282] Funding Source: KAKEN
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Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil, which is approved for the treatment of patients with metastatic colorectal cancer refractory to standard chemotherapies. A microRNA analysis of three colorectal cell lines was conducted to investigate causes of FTD resistance. Drug resistant sublines of DLD-1, HCT-116, and RKO cells were developed by continuous administration of increasing doses of FTD for 5 months. The let-7d-5p gene, which maps to chromosome 9q22.32, was downregulated in the FTD-resistant DLD-1 sublines. DLD-1 cells became more resistant to FTD when let-7d-5p was knocked down and more sensitive when let-7d-5p was overexpressed. The FTD-resistant sublines were not cross-resistant to 5-fluorouracil (5-FU); 5-FU sensitivity was affected only slightly when let-7d-5p was overexpressed or knocked down. These data indicate that let-7d-5p increases sensitivity of FTD but not 5-FU and that let-7d-5p is a potential clinical marker of treatment sensitivity.
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