Oncotarget

Research Papers:

MicroRNA profiles involved in trifluridine resistance

Kenta Tsunekuni, Masamitsu Konno, Ayumu Asai, Jun Koseki, Takashi Kobunai, Teiji Takechi, Yuichiro Doki, Masaki Mori _ and Hideshi Ishii

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Oncotarget. 2017; 8:53017-53027. https://doi.org/10.18632/oncotarget.18078

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Abstract

Kenta Tsunekuni1,2,3,*, Masamitsu Konno1,4,*, Ayumu Asai1,2,4, Jun Koseki2, Takashi Kobunai3, Teiji Takechi3, Yuichiro Doki1, Masaki Mori1 and Hideshi Ishii1,2

1Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan

2Department of Medical Data Science, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan

3Translational Research Laboratory, Taiho Pharmaceutical Co, Ltd, Tokushima City, Tokushima, 771-0194, Japan

4Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan

*These authors contributed equally to this work

Correspondence to:

Masaki Mori, email: mmori@gesurg.med.osaka-u.ac.jp

Hideshi Ishii, email: hishii@gesurg.med.osaka-u.ac.jp

Keywords: colorectal cancer, trifluridine, 5-fluorouracil, let-7d-5p, drug resistance

Received: March 28, 2017     Accepted: May 09, 2017     Published: May 23, 2017

ABSTRACT

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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