Skip to main content

Advertisement

SpringerLink
Log in

Sunitinib, Hypertension, and Heart Failure: A Model for Kinase Inhibitor-Mediated Cardiotoxicity

  • Mediators, Mechanisms in Tissue Injury (Heinrich Taegtmeyer, Steven A. Atlas, Section Editors)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Kinase inhibitors have emerged as an important new class of agents for the treatment of diverse tumors. Sunitinib malate is a small-molecule, oral, multi-kinase inhibitor approved for use in treating renal cell carcinoma and gastrointestinal stromal tumor. It has also demonstrated efficacy in treating pancreatic neuroendocrine tumors and is being evaluated for the treatment of other cancers. Initially developed for its inhibition of the vascular endothelial growth factor (VEGF) signaling pathway, sunitinib has been associated with hypertension and heart failure. This review examines the incidence and severity of these adverse events, relevant findings from other agents that inhibit VEGF signaling, the mechanisms underlying these effects, and suggestions for their clinical management. Hypertension is a common adverse effect that is usually easily managed. The associated heart failure is less common; it can be reversible but must be actively monitored and managed. Mechanistic insights suggest that an attentive clinical strategy for hypertension could prevent severe cardiotoxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. New Engl J Med. 2007;356(2):115–24.

    Article  PubMed  CAS  Google Scholar 

  2. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–38.

    Article  PubMed  CAS  Google Scholar 

  3. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New Engl J Med. 2011;364(6):501–13.

    Article  PubMed  CAS  Google Scholar 

  4. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370(9604):2011–9.

    Article  PubMed  CAS  Google Scholar 

  5. Chintalgattu V, Patel SS, Khakoo AY. Cardiovascular effects of tyrosine kinase inhibitors used for gastrointestinal stromal tumors. Hematol Oncol Clin North Am. 2009;23(1):97–107. viii-ix.

    Article  PubMed  Google Scholar 

  6. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Canc. 2009;9(1):28–39.

    Article  Google Scholar 

  7. Cheng H, Force T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res. 2010;106(1):21–34.

    Article  PubMed  CAS  Google Scholar 

  8. Force T, Kolaja KL. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat Rev Drug Discov. 2011;10(2):111–26.

    Article  PubMed  CAS  Google Scholar 

  9. Rees ML, Khakoo AY. Molecular mechanisms of hypertension and heart failure due to antiangiogenic cancer therapies. Heart Fail Clin. 2011;7(3):299–311.

    Article  PubMed  Google Scholar 

  10. Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol. 2009;48(1):9–17.

    Article  PubMed  CAS  Google Scholar 

  11. Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Canc Inst. 2011;103(9):763–73.

    Article  CAS  Google Scholar 

  12. Maitland ML, Kasza KE, Karrison T, et al. Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin Canc Res. 2009;15(19):6250–7.

    Article  CAS  Google Scholar 

  13. •• Azizi M, Chedid A, Oudard S. Home blood-pressure monitoring in patients receiving sunitinib. New Engl J Med. 2008;358(1):95–7. This study demonstrated the potential for blood pressure as a pharmacodynamic marker of sunitinib. It was the first study to clearly demonstrate the return of blood pressure to baseline levels with sunitinib withdrawal.

    Article  PubMed  CAS  Google Scholar 

  14. Facemire CS, Nixon AB, Griffiths R, et al. Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression. Hypertension. 2009;54(3):652–8.

    Article  PubMed  CAS  Google Scholar 

  15. Robinson ES, Khankin EV, Choueiri TK, et al. Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors. Hypertension. 2010;56(6):1131–6.

    Article  PubMed  CAS  Google Scholar 

  16. • Mourad JJ, des Guetz G, Debbabi H, Levy BI. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol. 2008;19(5):927–34. This study demonstrated that capillary rarefaction occurs in human patients after prolonged treatment with a regimen containing bevacizumab.

    Article  PubMed  Google Scholar 

  17. Kamba T, Tam BY, Hashizume H, et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006;290(2):H560–76.

    Article  PubMed  CAS  Google Scholar 

  18. Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2008;26(32):5204–12.

    Article  PubMed  Google Scholar 

  19. Choueiri TK, Mayer EL, Je Y, et al. Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol. 2011;29(6):632–8.

    Article  PubMed  CAS  Google Scholar 

  20. McArthur HL, Rugo H, Nulsen B, et al. A feasibility study of bevacizumab plus dose-dense doxorubicin-cyclophosphamide (AC) followed by nanoparticle albumin-bound paclitaxel in early-stage breast cancer. Clin Canc Res. 2011;17(10):3398–407.

    Article  CAS  Google Scholar 

  21. •• Chintalgattu V, Ai D, Langley RR, et al. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J Clin Investig. 2010;120(2):472–84. This mechanistic study demonstrated the importance of PDGF signaling in cardiac response to afterload stress and forms the basis for the “two-hit” hypothesis of KI-associated cardiac toxicity.

    Article  PubMed  CAS  Google Scholar 

  22. Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127–32.

    Article  PubMed  CAS  Google Scholar 

  23. Ghoreschi K, Laurence A, O’Shea JJ. Selectivity and therapeutic inhibition of kinases: to be or not to be? Nat Immunol. 2009;10(4):356–60.

    Article  PubMed  CAS  Google Scholar 

  24. Kerkela R, Woulfe KC, Durand JB, et al. Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin Transl Sci. 2009;2(1):15–25.

    Article  PubMed  CAS  Google Scholar 

  25. •• Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Canc Inst. 2010;102(9):596–604. This article provides a more comprehensive rationale for blood pressure control in patients receiving VEGF signaling pathway inhibitors.

    Article  CAS  Google Scholar 

  26. Langenberg MH, van Herpen CM, De Bono J, et al. Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of Cediranib in patients with advanced solid tumors. J Clin Oncol. 2009;27(36):6152–9.

    Article  PubMed  CAS  Google Scholar 

  27. • Dahlberg SE, Sandler AB, Brahmer JR, et al. Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol. 2010;28(6):949–54. Many prior publications reported an association between hypertension and therapeutic effects of VEGF signaling inhibitors. This analysis relied on intravenously administered bevacizumab and an optimal “landmark analysis” interrogation and should be recognized as the first to demonstrate convincingly an association between blood pressure elevations and improved outcomes with this class of anticancer agents.

    Article  PubMed  CAS  Google Scholar 

  28. Curwen JO, Musgrove HL, Kendrew J, et al. Inhibition of vascular endothelial growth factor-a signaling induces hypertension: examining the effect of cediranib (recentin; AZD2171) treatment on blood pressure in rat and the use of concomitant antihypertensive therapy. Clin Canc Res. 2008;14(10):3124–31.

    Article  CAS  Google Scholar 

  29. Franklin PH, Banfor PN, Tapang P, et al. Effect of the multitargeted receptor tyrosine kinase inhibitor, ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylphenyl)urea], on blood pressure in conscious rats and mice: reversal with antihypertensive agents and effect on tumor growth inhibition. J Pharmacol Exp Ther. 2009;329(3):928–37.

    Article  PubMed  CAS  Google Scholar 

  30. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. New Engl J Med. 2007;356(2):125–34.

    Article  PubMed  CAS  Google Scholar 

  31. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8.

    Article  PubMed  CAS  Google Scholar 

  32. Arnold AM, Seymour L, Smylie M, et al. Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR$20. J Clin Oncol. 2007;25(27):4278–84.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Conflicts of Interest: R. Gupta: none; M. Maitland: consulting fees from Pfizer on safety and development of anticancer agents others than sunitinib; co-inventor on a patent for use of the kinase inhibitor sorafenib in treating pulmonary hypertension.

Author information

Authors and Affiliations

  1. Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Avenue, MC2115, Chicago, IL, 60637, USA

    Michael L. Maitland

  2. Division of Cardiology and Feinberg Cardiovascular Research Institute, Northwestern University, 303 East Chicago Avenue, Tarry 14-759, Chicago, IL, 60611, USA

    Rajesh Gupta

Authors
  1. Rajesh Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael L. Maitland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael L. Maitland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gupta, R., Maitland, M.L. Sunitinib, Hypertension, and Heart Failure: A Model for Kinase Inhibitor-Mediated Cardiotoxicity. Curr Hypertens Rep 13, 430–435 (2011). https://doi.org/10.1007/s11906-011-0229-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-011-0229-4

Keywords

Search

Navigation