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Cardiovascular Safety of Tyrosine Kinase Inhibitors: With a Special Focus on Cardiac Repolarisation (QT Interval)

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Abstract

The development of tyrosine kinase inhibitors (TKI) represents a major milestone in oncology. However, their use has been found to be associated with serious toxicities that impinge on various vital organs including the heart. Sixteen TKIs have been approved for use in oncology as of 30 September 2012, and a large number of others are in development or under regulatory review. Cardiovascular safety of medicinal products is a major public health issue that has concerned all the stakeholders. This review focuses on three specific cardiovascular safety aspects of TKIs, namely their propensity to induce QT interval prolongation, left ventricular (LV) dysfunction and hypertension (both systemic and pulmonary). Analyses of information in drug labels, the data submitted to the regulatory authorities and the published literature show that a number of TKIs are associated with these undesirable effects. Whereas LV dysfunction and systemic hypertension are on-target effects related to the inhibition of ligand-related signalling pathways, QT interval prolongation appears to be an off-target class III electrophysiologic effect, possibly related to the presence of a fluorine-based pharmacophore. If not adequately managed, these cardiovascular effects significantly increase the morbidity and mortality in a population already at high risk. Hitherto, the QT effect of most QT-prolonging TKIs (except lapatinib, nilotinib, sunitinib and vandetanib) is relatively mild at clinical doses and has not led to appreciable morbidity clinically. In contrast, LV dysfunction and untreated hypertension have resulted in significant morbidity. Inevitably, dilemmas arise in determining the risk/benefit of a TKI therapy in an individual patient who develops any of these effects following the treatment of the TKI-sensitive cancer. QT interval prolongation, hypertension and LV dysfunction can be managed effectively by using reliable methods of measurement and careful monitoring of patients whose clinical management requires optimisation by a close collaboration between an oncologist and a cardiologist, an evolving subspecialty referred to as cardio-oncology. Despite their potential adverse clinical impact, the effects of TKIs on hypertension and LV function are generally inadequately characterised during their development. As has been the case with QT liability of drugs, there is now a persuasive case for a regulatory requirement to study TKIs systematically for these effects. Furthermore, since most of these novel drugs are studied in trials with relatively small sample sizes and approved on an expedited basis, there is also a compelling case for their effective pharmacovigilance and on-going reassessment of their risk/benefit after approval.

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References

  1. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353:172–87.

    Article  PubMed  CAS  Google Scholar 

  2. Strevel EL, Siu LL. Cardiovascular toxicity of molecularly targeted agents. Eur J Cancer. 2009;45(Suppl 1):318–31.

    Article  PubMed  Google Scholar 

  3. des Guetz G, Uzzan B, Chouahnia K, et al. Cardiovascular toxicity of anti-angiogenic drugs. Target Oncol. 2011;6:197–202.

    Article  PubMed  Google Scholar 

  4. Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol. 2002;54:188–202.

    Article  PubMed  CAS  Google Scholar 

  5. Shah RR. Cardiac repolarisation and drug regulation: assessing cardiac safety 10 years after the CPMP guidance. Drug Saf. 2007;30:1093–110.

    Article  PubMed  Google Scholar 

  6. Shah RR. Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter? Br J Clin Pharmacol. 2013;75:347–58.

    Article  PubMed  Google Scholar 

  7. Committee for Medicinal Products for Human Use. ICH note for guidance: the nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals (ICH S7B) (CHMP/ICH/423/02). EMA, London (2005). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002841.pdf (Accessed Sep 22 2012).

  8. Committee for Medicinal Products for Human Use. ICH note for guidance: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (ICH E14) (CHMP/ICH/2/04). EMA, London (2005). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002879.pdf (Accessed Sep 22 2012).

  9. Strevel EL, Ing DJ, Siu LL. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol. 2007;25:3362–71.

    Article  PubMed  CAS  Google Scholar 

  10. Ederhy S, Cohen A, Dufaitre G, et al. QT interval prolongation among patients treated with angiogenesis inhibitors. Target Oncol. 2009;4:89–97.

    Article  PubMed  Google Scholar 

  11. Garcia-Alvarez A, Garcia-Albeniz X, Esteve J, Rovira M, et al. Cardiotoxicity of tyrosine-kinase-targeting drugs. Cardiovasc Hematol Agents Med Chem. 2010;8:11–21.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Qi WX, Min DL, Shen Z, et al. Risk of venous thromboembolic events associated with VEGFR-TKIs: a systematic review and meta-analysis. Int J Cancer 2012 (Epub ahead of print).

  14. Sonpavde G, Je Y, Schutz F, et al. Venous thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol. 2013 (Epub ahead of print).

  15. Choueiri TK, Schutz FA, Je Y, et al. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28:2280–5.

    Article  PubMed  CAS  Google Scholar 

  16. Schutz FA, Je Y, Richards CJ, et al. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol. 2012;30:871–7.

    Article  PubMed  CAS  Google Scholar 

  17. Food and Drug Administration Product Reviews and Labels. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (Accessed Oct 28 2012).

  18. Food and Drug Administration Oncologic Drugs Advisory Committee Documents. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/default.htm (Accessed Oct 28 2012).

  19. European Medicines Agency European Public Assessment Reports Assessment History and Product Information. http://www.emea.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124 (Accessed Oct 28 2012).

  20. Health Canada Summary Basis of Decision. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/index-eng.php (Accessed Oct 28 2012).

  21. National Cancer Institute NCI Drug Dictionary. http://www.cancer.gov/drugdictionary (Accessed Oct 28 2012). doi:10.1007/s40264-013-0050-x

  22. Chen MH, Kerkela R, Force T. Mechanisms of cardiomyopathy associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118:84–95.

    Article  PubMed  Google Scholar 

  23. Force T. Introduction to cardiotoxicity reviews. Circ Res. 2010;106:19–20.

    Article  PubMed  CAS  Google Scholar 

  24. Scheffler M, Di Gion P, Doroshyenko O, et al. Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on 4-anilinoquinazolines. Clin Pharmacokinet. 2011;50:371–403.

    Article  PubMed  CAS  Google Scholar 

  25. Di Gion P, Kanefendt F, Lindauer A, et al. Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. Clin Pharmacokinet. 2011;50:551–603.

    Article  PubMed  Google Scholar 

  26. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9:28–39.

    Article  PubMed  Google Scholar 

  27. van Cruijsen H, van der Veldt A, Hoekman K. Tyrosine kinase inhibitors of VEGF receptors: clinical issues and remaining questions. Front Biosci. 2009;14:2248–68.

    Article  PubMed  Google Scholar 

  28. Roodhart JM, Langenberg MH, Witteveen E, et al. The molecular basis of class side effects due to treatment with inhibitors of the VEGF/VEGFR pathway. Curr Clin Pharmacol. 2008;3:132–43.

    Article  PubMed  CAS  Google Scholar 

  29. Shah DR, Shah RR, Morganroth J. Tyrosine kinase inhibitors: Their on-target toxicities as potential indicators of efficacy. Drug Saf. 2013 (in press).

  30. Asnacios A, Naveau S, Perlemuter G. Gastrointestinal toxicities of novel agents in cancer therapy. Eur J Cancer. 2009;45(Suppl 1):332–42.

    Article  PubMed  Google Scholar 

  31. Dienstmann R, Braña I, Rodon J, et al. Toxicity as a biomarker of efficacy of molecular targeted therapies: focus on EGFR and VEGF inhibiting anticancer drugs. Oncologist. 2011;16:1729–40.

    Article  PubMed  CAS  Google Scholar 

  32. Lu Z, Wu CY, Jiang YP, et al. Suppression of phosphoinositide 3-kinase signalling and alteration of multiple ion currents in drug-induced long QT syndrome. Sci Transl Med. 2012;4:131ra50.

    Article  PubMed  Google Scholar 

  33. Amir E, Seruga B, Martinez-Lopez J, et al. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol. 2011;29:2543–9.

    Article  PubMed  Google Scholar 

  34. Shah RR, Roberts SA, Shah DR. A fresh perspective on comparing the FDA and the CHMP/EMA: approval of antineoplastic tyrosine kinase inhibitors. Br J Clin Pharmacol. 2013. doi:10.1111/bcp.12085.

  35. Sanguinetti MC, Jiang C, Curran ME, et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81:299–307.

    Article  PubMed  CAS  Google Scholar 

  36. Vandenberg JI, Perry MD, Perrin MJ, et al. hERG K(+) channels: structure, function, and clinical significance. Physiol Rev. 2012;92:1393–478.

    Article  PubMed  CAS  Google Scholar 

  37. Milon D, Daubert JC, Saint-Marc C, et al. Torsade depointes. Apropos of 54 cases [Article in French]. Ann Fr Anesth Reanim. 1982;1:513–20.

    Article  PubMed  CAS  Google Scholar 

  38. Salle P, Rey JL, Bernasconi P, et al. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris). 1985;34:381–8.

    CAS  Google Scholar 

  39. Fung MC, Hsiao-hui Wu H, Kwong K, et al. Evaluation of the profile of patients with QTc prolongation in spontaneous adverse event reporting over the past three decades—1969–98. Pharmacoepidemiol Drug Saf. 2000;9(Suppl 1):S24.

    Google Scholar 

  40. Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol. 2008;48:13–8.

    Article  PubMed  CAS  Google Scholar 

  41. Rock EP, Finkle J, Fingert HJ, et al. Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J. 2009;157:827–36.

    Article  PubMed  CAS  Google Scholar 

  42. Morganroth J, Shah RR, Scott JW. Evaluation and management of cardiac safety using the electrocardiogram in oncology clinical trials: focus on cardiac repolarization (QTc interval). Clin Pharmacol Ther. 2010;87:166–74.

    Article  PubMed  CAS  Google Scholar 

  43. Shah RR, Morganroth J. Early investigation of QTc liability: the role of multiple ascending dose (MAD) study. Drug Saf. 2012;35:695–709.

    PubMed  CAS  Google Scholar 

  44. Piekarz RL, Frye AR, Wright JJ, et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res. 2006;12:3762–73.

    Article  PubMed  CAS  Google Scholar 

  45. Varterasian M, Meyer M, Fingert H, et al. Baseline heart rate-corrected QT and eligibility for clinical trials in oncology. J Clin Oncol. 2003;21:3378–9.

    Article  PubMed  Google Scholar 

  46. Dong Q, Fu XX, Du LL, et al. Blocking of the human ether-à-go-go-related gene channel by imatinib mesylate. Biol Pharm Bull. 2013;36:268–75.

    Article  PubMed  CAS  Google Scholar 

  47. Dogan E, Yorgun H, Petekkaya I, et al. Evaluation of cardiac safety of lapatinib therapy for ErbB2-positive metastatic breast cancer: a single center experience. Med Oncol. 2012;29:3232–9.

    Article  PubMed  CAS  Google Scholar 

  48. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633–40.

    Article  PubMed  CAS  Google Scholar 

  49. Kim TD, le Coutre P, Schwarz M, et al. Clinical cardiac safety profile of nilotinib. Haematologica. 2012;97:883–9.

    Article  PubMed  CAS  Google Scholar 

  50. AstraZeneca CAPRELSA REMS Program. http://www.caprelsarems.com/learn.aspx (Accessed Jan 20 2013).

  51. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897–905.

    Article  PubMed  CAS  Google Scholar 

  52. Zang J, Wu S, Tang L, et al. Incidence and risk of QTc interval prolongation among cancer patients treated with vandetanib: a systematic review and meta-analysis. PLoS One. 2012;7:e30353.

    Article  PubMed  CAS  Google Scholar 

  53. Barros F, Gomez-Varela D, Viloria CG, et al. Modulation of human erg K+ channel gating by activation of a G protein-coupled receptor and protein kinase C. J Physiol. 1998;511(Pt 2):333–46.

    Article  PubMed  CAS  Google Scholar 

  54. Thomas D, Zhang W, Karle CA, et al. Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A. J Biol Chem. 1999;274:27457–62.

    Article  PubMed  CAS  Google Scholar 

  55. Kiehn J, Karle C, Thomas D, et al. HERG potassium channel activation is shifted by phorbol esters via protein kinase A-dependent pathways. J Biol Chem. 1998;273:25285–91.

    Article  PubMed  CAS  Google Scholar 

  56. Davis MJ, Wu X, Nurkiewicz TR, et al. Regulation of ion channels by protein tyrosine phosphorylation. Am J Physiol Heart Circ Physiol. 2001;281:H1835–62.

    PubMed  CAS  Google Scholar 

  57. Marx SO, Kurokawa J, Reiken S, et al. Requirement of a macromolecular signalling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science. 2002;295:496–9.

    Article  PubMed  CAS  Google Scholar 

  58. Chen J, Sroubek J, Krishnan Y, et al. PKA phosphorylation of HERG protein regulates the rate of channel synthesis. Am J Physiol Heart Circ Physiol. 2009;296:H1244–54.

    Article  PubMed  CAS  Google Scholar 

  59. Sroubek J, McDonald TV. Protein kinase A activity at the endoplasmic reticulum surface is responsible for augmentation of human ether-a-go-go-related gene product (HERG). J Biol Chem. 2011;286:21927–36.

    Article  PubMed  CAS  Google Scholar 

  60. Krishnan Y, Li Y, Zheng R, et al. Mechanisms underlying the protein-kinase mediated regulation of the HERG potassium channel synthesis. Biochim Biophys Acta. 2012;1823:1273–84.

    Article  PubMed  CAS  Google Scholar 

  61. Zhang Y, Wang H, Wang J, et al. Normal function of HERG K+ channels expressed in HEK293 cells requires basal protein kinase B activity. FEBS Lett. 2003;534:125–32.

    Article  PubMed  CAS  Google Scholar 

  62. Zhang DY, Wang Y, Lau CP, et al. Both EGFR kinase and Src-related tyrosine kinases regulate human ether-à-go-go-related gene potassium channels. Cell Signal. 2008;20:1815–21.

    Article  PubMed  CAS  Google Scholar 

  63. Himmel HM, Hoffmann M. QTc shortening with a new investigational cancer drug: a brief case study. J Pharmacol Toxicol Methods. 2010;62:72–81.

    Article  PubMed  CAS  Google Scholar 

  64. Morgan TK Jr, Sullivan ME. An overview of class III electrophysiological agents: a new generation of antiarrhythmic therapy. Prog Med Chem. 1992;29:65–108.

    Article  PubMed  CAS  Google Scholar 

  65. Park BK, Kitteringham NR. Effects of fluorine substitution on drug metabolism: pharmacological and toxicological implications. Drug Metab Rev. 1994;26:605–43.

    Article  PubMed  CAS  Google Scholar 

  66. Park BK, Kitteringham NR, O’Neill PM. Metabolism of fluorine-containing drugs. Annu Rev Pharmacol Toxicol. 2001;41:443–70.

    Article  PubMed  CAS  Google Scholar 

  67. Elice F, Rodeghiero F, Falanga A, et al. Thrombosis associated with angiogenesis inhibitors. Best Pract Res Clin Haematol. 2009;22:115–28.

    Article  PubMed  CAS  Google Scholar 

  68. Girardi F, Franceschi E, Brandes AA. Cardiovascular safety of VEGF-targeting therapies: current evidence and handling strategies. Oncologist. 2010;15:683–94.

    Article  PubMed  CAS  Google Scholar 

  69. Minami M, Matsumoto S, Horiuchi H. Cardiovascular side-effects of modern cancer therapy. Circ J. 2010;74:1779–86.

    Article  PubMed  CAS  Google Scholar 

  70. Keefe D, Bowen J, Gibson R, et al. Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. Oncologist. 2011;16:432–44.

    Article  PubMed  CAS  Google Scholar 

  71. Mellor HR, Bell AR, Valentin JP, et al. Cardiotoxicity associated with targeting kinase pathways in cancer. Toxicol Sci. 2011;120:14–32.

    Article  PubMed  CAS  Google Scholar 

  72. Sonpavde G, Bellmunt J, Schutz F, et al. The double edged sword of bleeding and clotting from VEGF inhibition in renal cancer patients. Curr Oncol Rep. 2012;14:295–306.

    Article  PubMed  CAS  Google Scholar 

  73. Mir O, Ropert S, Alexandre J, et al. Hypertension as a surrogate marker for the activity of anti-VEGF agents. Ann Oncol. 2009;20:967–70.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Qi WX, Shen Z, Lin F, et al. Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials. Br J Clin Pharmacol. 2012;75:919–30.

    Article  Google Scholar 

  76. Robinson ES, Khankin EV, Karumanchi SA, et al. Hypertension induced by vascular endothelial growth factor signalling pathway inhibition: mechanism and potential use as a biomarker. Semin Nephrol. 2010;30:591–601.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  78. Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006;24:1363–9.

    Article  PubMed  CAS  Google Scholar 

  79. Kim JJ, Vaziri SA, Rini BI, 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;118:1946–54.

    Article  PubMed  CAS  Google Scholar 

  80. Steeghs N, Gelderblom H, Roodt JO, et al. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res. 2008;14:3470–6.

    Article  PubMed  CAS  Google Scholar 

  81. GlaxoSmilthKline Clinical Study Register A meta-analysis of the cumulative incidence of hypertension in the first month of treatment with pazopanib across three RCC studies: VEG102616, VEG105192 and VEG107769 (Study number 115227). http://www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=115227&studyId=7FE7FADD-D3FA-4BD6-9BF5-0845FF2A2C90&compound=pazopanib&type=Compound&letterrange=L-P (Accessed Oct 25 2012).

  82. Quintás-Cardama A, Kantarjian H, O’brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25:3908–14.

    Article  PubMed  Google Scholar 

  83. Guignabert C, Montani D. Key roles of Src family tyrosine kinases in the integrity of the pulmonary vascular bed. Eur Respir J. 2013;41:3–4.

    Article  PubMed  CAS  Google Scholar 

  84. Pullamsetti SS, Berghausen EM, Dabral S, et al. Role of Src tyrosine kinases in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2012;32:1354–65.

    Article  PubMed  CAS  Google Scholar 

  85. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115:2811–21.

    Article  PubMed  CAS  Google Scholar 

  86. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med. 2005;353:1412–3.

    Article  PubMed  CAS  Google Scholar 

  87. Tapper EB, Knowles D, Heffron T, et al. Portopulmonary hypertension: imatinib as a novel treatment and the Emory experience with this condition. Transplant Proc. 2009;41:1969–71.

    Article  PubMed  CAS  Google Scholar 

  88. ten Freyhaus H, Dumitrescu D, Bovenschulte H, et al. Significant improvement of right ventricular function by imatinib mesylate in scleroderma-associated pulmonary arterial hypertension. Clin Res Cardiol. 2009;98:265–7.

    Article  PubMed  Google Scholar 

  89. Chhina MK, Nargues W, Grant GM, et al. Evaluation of imatinib mesylate in the treatment of pulmonary arterial hypertension. Future Cardiol. 2010;6:19–35.

    Article  PubMed  CAS  Google Scholar 

  90. ten Freyhaus H, Dumitrescu D, Berghausen E, et al. Imatinib mesylate for the treatment of pulmonary arterial hypertension. Expert Opin Investig Drugs. 2012;21:119–34.

    Article  PubMed  Google Scholar 

  91. Antoniu SA. Targeting PDGF pathway in pulmonary arterial hypertension. Expert Opin Ther Targets. 2012;16:1055–63.

    Article  PubMed  CAS  Google Scholar 

  92. Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182:1171–7.

    Article  PubMed  CAS  Google Scholar 

  93. Hatano M, Yao A, Shiga T, et al. Imatinib mesylate has the potential to exert its efficacy by down-regulating the plasma concentration of platelet-derived growth factor in patients with pulmonary arterial hypertension. Int Heart J. 2010;51:272–6.

    Article  PubMed  CAS  Google Scholar 

  94. Ciuclan L, Bonneau O, Hussey M, et al. A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2011;184:1171–82.

    Article  PubMed  CAS  Google Scholar 

  95. Ciuclan L, Hussey MJ, Burton V, et al. Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. Am J Respir Crit Care Med. 2013;187:78–89.

    Article  PubMed  CAS  Google Scholar 

  96. Kojonazarov B, Sydykov A, Pullamsetti SS, et al. Effects of multikinase inhibitors on pressure overload-induced right ventricular remodeling. Int J Cardiol. 2012 (Epub ahead of print).

  97. 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;26:5204–12.

    Article  PubMed  Google Scholar 

  98. Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908–16.

    Article  PubMed  Google Scholar 

  99. Lenihan DJ, Cardinale D, Cipolla CM. The compelling need for a cardiology and oncology partnership and the birth of the International CardiOncology Society. Prog Cardiovasc Dis. 2010;53:88–93.

    Article  PubMed  Google Scholar 

  100. Cheng H, Force T. Why do kinase inhibitors cause cardiotoxicity and what can be done about it? Prog Cardiovasc Dis. 2010;53:114–20.

    Article  PubMed  CAS  Google Scholar 

  101. Dasanu CA, Padmanabhan P, Clark BA 3rd, et al. Cardiovascular toxicity associated with small molecule tyrosine kinase inhibitors currently in clinical use. Expert Opin Drug Saf. 2012;11:445–57.

    Article  PubMed  CAS  Google Scholar 

  102. Montaigne D, Hurt C, Neviere R. Mitochondria death/survival signalling pathways in cardiotoxicity induced by anthracyclines and anticancer-targeted therapies. Biochem Res Int. 2012;Article ID 951539.

  103. Van den Akker NM, Winkel LC, Nisancioglu MH, et al. PDGF-B signalling is important for murine cardiac development: its role in developing atrioventricular valves, coronaries, and cardiac innervation. Dev Dyn. 2008;237:494–503.

    Article  PubMed  Google Scholar 

  104. Cheng H, Kari G, Dicker AP, et al. A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity. Circ Res. 2011;109:1401–9.

    Article  PubMed  CAS  Google Scholar 

  105. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibitors. Nat Rev Cancer. 2007;7:332–44.

    Article  PubMed  CAS  Google Scholar 

  106. 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;2:15–25.

    Article  PubMed  CAS  Google Scholar 

  107. Hasinoff BB. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity. Toxicol Appl Pharmacol. 2010;244:190–5.

    Article  PubMed  CAS  Google Scholar 

  108. Hasinoff BB, Patel D. Mechanisms of myocyte cytotoxicity induced by the multikinase inhibitor sorafenib. Cardiovasc Toxicol. 2010;10:1–8.

    Article  PubMed  CAS  Google Scholar 

  109. Hasinoff BB, Patel D. The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro. Toxicol Appl Pharmacol. 2010;249:132–9.

    Article  PubMed  CAS  Google Scholar 

  110. Subbiah IM, Lenihan DJ, Tsimberidou AM. Cardiovascular toxicity profiles of vascular-disrupting agents. Oncologist. 2011;16:1120–30.

    Article  PubMed  CAS  Google Scholar 

  111. Force T, Kerkela R. Cardiotoxicity of the new cancer therapeutics- mechanisms of, and approaches to, the problem. Drug Discov Today. 2008;13:778–84.

    Article  PubMed  CAS  Google Scholar 

  112. Yang B, Papoian T. Tyrosine kinase inhibitor (TKI)-induced cardiotoxicity: approaches to narrow the gaps between preclinical safety evaluation and clinical outcome. J Appl Toxicol. 2012 (Epub ahead of print).

  113. Eschenhagen T, Force T, Ewer MS, et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2011;13:1–10.

    Article  PubMed  Google Scholar 

  114. Steingart RM, Bakris GL, Chen HX, et al. Management of cardiac toxicity in patients receiving vascular endothelial growth factor signalling pathway inhibitors. Am Heart J. 2012;163:156–63.

    Article  PubMed  CAS  Google Scholar 

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Conflict of interest

The authors have no conflicts of interest that are directly relevant to the content of this review and have not received any financial support for writing it. RRS was formerly a Senior Clinical Assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), London, UK, and the ICH E14 Topic Leader, representing the EU. JM is the Chief Cardiac Consultant to eResearchTechnology Inc. (eRT), Philadelphia, PA, USA, which provides cardiac safety services to drug development companies. Both RRS and JM now provide expert consultancy services on QT liability of drugs and development of new drugs to a number of pharmaceutical companies. DRS is a first-year house officer at a district general hospital and has no consultancy relationships.

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Correspondence to Rashmi R. Shah.

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Shah, R.R., Morganroth, J. & Shah, D.R. Cardiovascular Safety of Tyrosine Kinase Inhibitors: With a Special Focus on Cardiac Repolarisation (QT Interval). Drug Saf 36, 295–316 (2013). https://doi.org/10.1007/s40264-013-0047-5

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