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Determinants of Gefitinib toxicity in advanced non-small cell lung cancer (NSCLC): a pharmacogenomic study of metabolic enzymes and transporters

The Pharmacogenomics Journal volume 17, pages 325–330 (2017)Cite this article

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Abstract

Skin rash, diarrhea and hepatotoxicity are the most common toxicities of Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The present study investigated the effects of genetic polymorphisms of drug target, metabolizing enzymes and transporters on Gefitinib toxicities. Thirty single-nucleotide polymorphisms, including EGFR, cytochromes P450 and ATP-binding cassette (ABC), were genotyped by matrix-assisted laser desorption/ionization time-of-flight platform in 59 non-small cell lung cancer patients treated with Gefitinib. Correlation analyses were performed to evaluate their effects on Gefitinib-induced toxicities. ABCB1 rs1128503 TT genotype was a significant high-risk determinant of both skin rash and diarrhea, with 15.78- and 10.78-fold of incident risk increased, respectively. (odds ratio (OR)=15.78, 95% confidence interval (CI) 2.01–124.1, P=0.0087; OR=10.78, 95% CI 1.54–75.40, P=0.0166 vs non-TT genotypes). Patients with ABCB1 rs1128503 TT genotype had greater risk of skin rash and diarrhea. Therefore, polymorphism analyses of ABCB1 might be beneficial to optimize Gefitinib treatment.

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Acknowledgements

This study was supported by National High Technology Research and Development Program of China (Grant No.: 2012AA02A502), and Innovative drug R&D center based on real-time high-throughput cell-based screening platform and large capacity compound library (Grant No.: 2013ZX09401003-002), and National Natural Science Funds of China (Grant No.: 81372502).

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Author notes

  1. Y Ma and S Xin: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Trial Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China

    Y Ma, H Zhao & Y Zhang

  2. Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China

    S Xin, M Huang, C Zhu, L Chen, J Li, W Zhuang, X Zhu & X Wang

  3. Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China

    Y Yang, Y Zhao & L Zhang

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  1. Y Ma
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Correspondence to L Zhang or X Wang.

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Ma, Y., Xin, S., Huang, M. et al. Determinants of Gefitinib toxicity in advanced non-small cell lung cancer (NSCLC): a pharmacogenomic study of metabolic enzymes and transporters. Pharmacogenomics J 17, 325–330 (2017). https://doi.org/10.1038/tpj.2016.31

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  • DOI: https://doi.org/10.1038/tpj.2016.31

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