Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma

The Pharmacogenomics Journal volume 17, pages 42–46 (2017)Cite this article

Subjects

Abstract

The single nucleotide polymorphism (SNP) rs4646437G>A in CYP3A4 was suggested to be related to sunitinib toxicity. Our objective was to perform an in-depth investigation of the association between this SNP and sunitinib toxicity and efficacy using a large cohort of metastatic renal cell carcinoma (mRCC) patients. We collected DNA and clinical information of mRCC patients treated with sunitinib. SNP rs4646437 in CYP3A4 was tested for associations with toxicity using logistic regression. Cox regression modeling was used for association analysis of rs4646437 with progression-free survival (PFS) and overall survival (OS). In a total of 287 patients, the A-allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension (odds ratio=2.4, 95% confidence interval: 1.1–5.2, P=0.021) and showed no significant association with PFS or OS. In conclusion, hypertension is more likely to occur in A-allele carriers of the CYP3A4 rs4646437 variant in our cohort of mRCC patients treated with sunitinib.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. van der Veldt A, Eechoute K, Gelderblom H, Gietema J, Guchelaar H-J, van Erp N et al. Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res 2011; 17: 620–629.

    Article  CAS  PubMed  Google Scholar 

  2. van Erp N, Eechoute K, van der Veldt A, Haanen J, Reyners A, Mathijssen R et al. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol 2009; 27: 4406–4412.

    Article  CAS  PubMed  Google Scholar 

  3. Garcia-Donas J, Esteban E, Leandro-Garcia L, Castellano D, del Alba A, Climent M et al. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol 2011; 12: 1143–1150.

    Article  CAS  PubMed  Google Scholar 

  4. Eechoute K, van der Veldt A, Oosting S, Kappers M, Wessels J, Gelderblom H et al. Polymorphisms in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) predict sunitinib-induced hypertension. Clin Pharmacol Ther 2012; 92: 503–510.

    CAS  PubMed  Google Scholar 

  5. Kim J, Vaziri S, Rini B, Elson P, Garcia J, Wirka R et al. Association of VEGF and VEGFR2 single nucleotide polymorphisms with hypertension and clinical outcome in metastatic clear cell renal cell carcinoma patients treated with sunitinib. Cancer 2012; 118: 1946–1954.

    Article  CAS  Google Scholar 

  6. Urun Y, Gray K, Signoretti S, McDermott D, Atkins M, Lampron M et al. Pharmacogenetics as predictor of sunitinib and mTOR inhibitors toxicity in patients with metastatic renal cell carcinoma (mRCC). ASCO Meeting Abstr 2013; 31http://meetinglibrary.asco.org/content/113157-132.

  7. He H, Sun J, Ren X, Wang T, Zhai Y, Chen S et al. Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole. Eur J Clin Microbiol Infect Dis 2015; 34: 811–819.

    Article  CAS  PubMed  Google Scholar 

  8. Li C, Li L, Lin L, Jiang H, Zhong Z, Li W et al. Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients. PLoS One 2014; 9: e86206.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Crettol S, Venetz J-P, Fontana M, Aubert J-D, Pascual M, Eap C et al. CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients. Ther Drug Monit 2008; 30: 689–699.

    Article  CAS  PubMed  Google Scholar 

  10. Schirmer M, Rosenberger A, Klein K, Kulle B, Toliat M, Nurnberg P et al. Sex-dependent genetic markers of CYP3A4 expression and activity in human liver microsomes. Pharmacogenomics J 2007; 8: 443–453.

    Article  CAS  Google Scholar 

  11. Diekstra M, Swen J, Boven E, Castellano D, Gelderblom H, Mathijssen R et al. CYP3A5 and ABCB1 polymorphisms as predictors for sunitinib outcome in metastatic renal cell carcinoma. Eur Urol 2015; 68: 621–629.

    Article  CAS  PubMed  Google Scholar 

  12. Heng D, Xie W, Regan M, Warren M, Golshayan A, Sahi C et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009; 27: 5794–5799.

    Article  CAS  PubMed  Google Scholar 

  13. Lankhorst S, Kappers M, van Esch J, Danser A, van den Meiracker A . Hypertension during vascular endothelial growth factor inhibition: focus on nitric oxide, endothelin-1, and oxidative stress. Antioxid Redox Signal 2014; 20: 135–145.

    Article  CAS  PubMed  Google Scholar 

  14. Houk B, Bello C, Poland B, Rosen L, Demetri G, Motzer R et al. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol 2010; 66: 357–371.

    Article  CAS  PubMed  Google Scholar 

  15. Mizuno T, Fukudo M, Terada T, Kamba T, Nakamura E, Ogawa O et al. Impact of genetic variation in breast cancer resistance protein (BCRP/ABCG2) on sunitinib pharmacokinetics. Drug Metab Pharmacokinet 2012; 27: 631–639.

    Article  CAS  PubMed  Google Scholar 

  16. Nagata M, Ishiwata Y, Takahashi Y, Takahashi H, Saito K, Fujii Y et al. Pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia in Japanese patients with renal cell carcinoma. Biol Pharm Bull 2015; 38: 402–410.

    Article  CAS  PubMed  Google Scholar 

  17. Noda S, Otsuji T, Baba M, Yoshida T, Kageyama S, Okamoto K et al. Assessment of sunitinib-induced toxicities and clinical outcomes based on therapeutic drug monitoring of sunitinib for patients with renal cell carcinoma. Clin Genitourin Cancer 2015; 13: 350–358.

    Article  PubMed  Google Scholar 

  18. Teo Y, Wee H, Chue X, Chau N, Tan M, Kanesvaran R et al. Effect of the CYP3A5 and ABCB1 genotype on exposure, clinical response and manifestation of toxicities from sunitinib in Asian patients. Pharmacogenomics J 2015; e-pub ahead of print 17 March 2015; doi:10.1038/tpj.2015.13.

    Article  PubMed  Google Scholar 

  19. Diekstra M, Klümpen HJ, Lolkema M, Yu H, Kloth J, Gelderblom H et al. Association analysis of genetic polymorphisms in genes related to sunitinib pharmacokinetics, specifically clearance of sunitinib and SU12662. Clin Pharmacol Ther 2014; 96: 81–89.

    Article  CAS  PubMed  Google Scholar 

  20. Rini B, Cohen D, Lu D, Chen I, Hariharan S, Gore M et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011; 103: 763–773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Beuselinck B, Lambrechts D, Van Brussel T, Wolter P, Cardinaels N, Joniau S et al. Efflux pump ABCB1 single nucleotide polymorphisms and dose reductions in patients with metastatic renal cell carcinoma treated with sunitinib. Acta Oncol 2014; 53: 1413–1422.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Tahar van der Straaten and Renée Baak-Pablo for their assistance with data management and genotyping. The European Union’s Seventh Framework Programme (FP7/2007–2013) supports Meta Diekstra under grant agreement no. 259939. This research is supported by Pfizer.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    M H Diekstra, J J Swen & H-J Guchelaar

  2. Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands

    M H Diekstra, J J Swen, E Boven, H Gelderblom, R H Mathijssen & H-J Guchelaar

  3. Department of Clinical Pharmacy, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain

    A Belaustegui

  4. Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

    E Boven

  5. Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain

    D Castellano

  6. Spanish Oncology Genitourinary Group, Madrid, Spain

    D Castellano & J García-Donas

  7. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands

    H Gelderblom

  8. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    R H Mathijssen

  9. Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain

    J García-Donas

  10. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, Madrid, Spain

    C Rodríguez-Antona

  11. ISCIII Center for Biomedical Research on Rare Diseases, Madrid, Spain

    C Rodríguez-Antona

  12. Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA

    B I Rini

Authors
  1. M H Diekstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Belaustegui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J J Swen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Boven
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Castellano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Gelderblom
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R H Mathijssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J García-Donas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Rodríguez-Antona
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. B I Rini
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H-J Guchelaar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H-J Guchelaar.

Ethics declarations

Competing interests

Brian Rini and Garcia-Donas report consulting and research funding from Pfizer. The other authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Diekstra, M., Belaustegui, A., Swen, J. et al. Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma. Pharmacogenomics J 17, 42–46 (2017). https://doi.org/10.1038/tpj.2015.100

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.100

This article is cited by

Search

Advanced search

Quick links