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Genetic variations in the ATP-binding cassette transporter ABCC10 are associated with neutropenia in Japanese patients with lung cancer treated with nanoparticle albumin-bound paclitaxel

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Abstract

ABCC10/MRP7, an ATP-binding cassette (ABC) transporter, has been implicated in the extracellular transport of taxanes. Our group reported that the ABCC10 single nucleotide polymorphism (SNPs), rs2125739, influences docetaxel cytotoxicity in lung cancer cell lines as well as its side effects in clinical practice. In this study, we investigated whether the rs2125739 variant could affect paclitaxel (PTX) cytotoxicity in lung cancer cell lines. We also investigated the effect of rs2125739 on the efficacy and safety of nanoparticle albumin-bound PTX (nab-PTX) in clinical practice. The association between rs2125739 genotypes and the 50% inhibitory concentration (IC50) of PTX was investigated in 18 non-small cell lung cancer (NSCLC) cell lines, HeLa cells, and genome-edited HeLa cells. Next, blood samples from 77 patients with NSCLC treated with carboplatin plus nab-PTX were collected and analyzed for six SNPs, including rs2125739. The clinical outcomes among the different genotype groups were evaluated. In NSCLC cell lines, HeLa cells, and genome-edited HeLa cells, the IC50 was significantly higher in the ABCC10 rs2125739 T/T group than in the T/C and C/C groups. In 77 patients with NSCLC, there were no significant differences in clinical outcomes between the T/T and T/C groups. However, the rs2125739 T/T genotype was associated with a higher frequency of Grades 3/4 neutropenia. In contrast, there was no association between other SNPs and clinical efficacy or neutropenia. Our results indicate that the ABCC10 rs2125739 variant is associated with neutropenia in response to nab-PTX treatment.

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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed MINORU HORIUCHI and TAKEHIRO UEMURA. The first draft of the manuscript was written by MINORU HORIUCHI, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Acknowledgements

We would like to acknowledge the contributions of all patients included in this study.

Funding

This study was supported by a Grant-in-Aid from Nagoya City University Foundation. (2015. No.6). We used this grant for cell line experiments. The funding body was not involved in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Authors and Affiliations

  1. Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Minoru Horiuchi, Takehiro Uemura, Tetsuya Oguri, Sanae Toda, Sayaka Yamamoto, Yuto Suzuki, Yusuke Kagawa, Kazuki Sone, Satoshi Fukuda, Yuta Mori, Kensuke Fukumitsu, Yoshihiro Kanemitsu, Tomoko Tajiri, Hirotsugu Ohkubo, Masaya Takemura, Yutaka Ito, Ken Maeno & Akio Niimi

  2. Department of Education and Research Center for Community Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Tetsuya Oguri & Masaya Takemura

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  1. Minoru Horiuchi
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed MINORU HORIUCHI and TAKEHIRO UEMURA. The first draft of the manuscript was written by MINORU HORIUCHI, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Takehiro Uemura.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Nagoya City University (No. 70–00-0095).

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Horiuchi, M., Uemura, T., Oguri, T. et al. Genetic variations in the ATP-binding cassette transporter ABCC10 are associated with neutropenia in Japanese patients with lung cancer treated with nanoparticle albumin-bound paclitaxel. Invest New Drugs 40, 934–943 (2022). https://doi.org/10.1007/s10637-022-01275-x

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