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ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer

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Abstract

Purpose

ABCC11/MRP8 (ABCC11) is an ATP-binding cassette transporter that is involved in regulating cellular sensitivity and resistance for many anti-cancer drugs. Since 5-fluorouracil (5-FU) is one of the substrates for ABCC11, we examined whether ABCC11 is a predictive marker for an oral 5-FU derivative drug S-1 treatment in non-small cell lung cancer (NSCLC).

Methods

Real-time PCR and MTS assay were carried on 21 human NSCLC cell lines. The drug resistance capabilities of ABCC11 are evaluated by analyzing the resistance profiles of a clone of HeLa cell in which the pump was ectopically expressed. Blood samples of 106 NSCLC patients were collected.

Results

There was a significant correlation between dihydropyrimidine dehydrogenase (DPD) gene expression and the IC50 for 5-FU. We then classified NSCLC cell lines into two groups based on the phenotype of the SNP538 (G > A) in ABCC11: a combined G/G and G/A group, and an A/A group. The distribution of the IC50 for 5-FU in combination with a potent inhibitor of DPD 5-chloro-2, 4-dihydropyrimidine (CDHP), which is contained in S-1, showed a significant reduction in the A/A group compared with the combined G/G and G/A group. Next, the clinical usefulness of the ABCC11 SNP in treatment containing S-1 was examined in 106 NSCLC patients, and the disease control rate was found to be significantly better in the A/A group than in the combined G/G and G/A group.

Conclusions

These results indicate that the SNP538(G > A) in the ABCC11 gene is a potential determinant for S-1 treatment.

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Acknowledgements

This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (MEXT/JSPSKAKENHI23591156).

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Authors and Affiliations

  1. Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

    Takehiro Uemura, Ken Maeno, Kazuki Sone, Akira Takeuchi, Satoshi Fukuda, Osamu Takakuwa, Yoshihiro Kanemitsu, Hirotsugu Ohkubo, Masaya Takemura, Yutaka Ito & Akio Niimi

  2. Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan

    Takehiro Uemura

  3. Education and Research Center for Community Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

    Tetsuya Oguri

  4. Department of Respiratory Medicine, Nagoya City West Medical Center, 1-1-1, Hirate-cho, Kita-ku, Nagoya, 462-8508, Japan

    Eiji Kunii

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  1. Takehiro Uemura
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Correspondence to Tetsuya Oguri.

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Uemura, T., Oguri, T., Maeno, K. et al. ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer. Cancer Chemother Pharmacol 84, 1229–1239 (2019). https://doi.org/10.1007/s00280-019-03959-3

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