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Polymorphisms of NF-κB pathway genes influence adverse drug reactions of gefitinib in NSCLC patients

The Pharmacogenomics Journal volume 20, pages 285–293 (2020)Cite this article

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Abstract

Gefitinib is a widely used targeted therapeutic drug in East Asian non-small cell lung cancer (NSCLC) patients. This research retrospectively investigated the relationship between the polymorphisms of genes involved in NF-κB pathways and gefitinib-related Adverse Drug Reactions (ADRs). From 2011 to 2016, 109 NSCLC patients were enrolled in this study. Thirty-two SNPs of 15 genes were genotyped with a Sequenom MassARRAY system. We collected 34 paired RNA samples before and after gefitinib administration for the detection of whole blood RNA expression of genes in NF-κB pathways (NFKBIA, NFKB1, NFKB2, RELA, RELB, and TNFAIP3). IKBKB rs2272733 (CC vs non-CC: OR = 0.256, 95% CI 0.087–0.753, P = 0.013) and IKBKE rs12142086 (CC vs non-CC: OR = 3.640, 95% CI 1.320–10.039, P = 0.013) were significantly associated with gefitinib-induced skin toxicity. IKBKE rs2151222 was associated with diarrhea with the odds ratio of non-TT vs TT as 0.162 (non-TT vs TT: 95% CI 0.034–0.775, P = 0.023). Furthermore, RELA rs11227247 was a predictor for hepatic toxicity (GG vs non-GG: OR = 0.212, 95% CI 0.062–0.726, P = 0.013). None of the gene expression levels after drug administration were determined to be significant predictors for adverse drug reactions by a logistics regression analysis. Polymorphisms of IKBKB, IKBKE, and RELA are potential biomarkers for predicting gefitinib-related ADRs. Further studies are needed to understand the underlying mechanisms for diagnostic and prophylactic therapy applications.

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Data availability

The datasets generated and/or analyzed during the current study are not publicly available due China Human Genetic Resources Regulations but are available from the corresponding author on reasonable request. All statistical analyses were performed using R (version 3.2.4). The computer codes are available from the corresponding author by e-mail on reasonable request.

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Acknowledgements

This work was supported by the National Nature Science Foundation of China [nos. 81973398 and 81473283]; and the National Key R&D Program of China [2016YFC0905003, 2016YFC0905503, 2017YFC0909303]; and Science and Technology Program of Guangdong Province [2017B020227001, 201607020031]; and the 111 Project, no. B16047; and Science, Technology and Innovation Commission of Shenzhen Municipality under grant no. JCYJ20170817145454378; and Open Fund for South China State Key Laboratory of Oncology [HN2017-06].

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  1. These authors contributed equally: Shuang Xin, Yuanyuan Zhao

Authors and Affiliations

  1. Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, 510060, Guangzhou, China

    Shuang Xin, Wei Zhuang, Min Huang & Xueding Wang

  2. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 510060, Guangzhou, China

    Shuang Xin, Yuanyuan Zhao, Yan Huang, Yuxiang Ma & Li Zhang

  3. BGI-Shenzhen, 518083, Shenzhen, China

    Shuang Xin, Changzheng Wang & Xun Xu

  4. University of Chinese Academy of Sciences, 518083, Shenzhen, China

    Changzheng Wang

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  1. Shuang Xin
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Contributions

XDW, LZ, XX, and MH, conceived and planned the experiments. SX, and WZ carried out the experiments. YYZ, YH, and YXM contributed to sample preparation and clinical data collection. CZW carried out the data analysis. SX and YYZ. took the lead in writing the paper and the results. All authors provided critical feedback and helped shape the research, analysis, andpaper.

Corresponding authors

Correspondence to Xueding Wang or Li Zhang.

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The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Ethical Committee of Sun Yat-Sen University Cancer Center (B2013-08-01).

Informed consent

Written informed consent was obtained from all participating subjects. This trial was registered at ClinicalTrials.gov. (NCT01994057).

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Xin, S., Zhao, Y., Wang, C. et al. Polymorphisms of NF-κB pathway genes influence adverse drug reactions of gefitinib in NSCLC patients. Pharmacogenomics J 20, 285–293 (2020). https://doi.org/10.1038/s41397-019-0115-z

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