BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis?

Abstract

Imatinib, the first-in-class BCR-ABL tyrosine kinase inhibitor (TKI), had been a revolution for the treatment of chronic myeloid leukemia (CML) and had greatly enhanced patient survival. Second- (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKIs have been developed to be effective against BCR-ABL mutations making imatinib less effective. However, these treatments have been associated with arterial occlusive events. This review gathers clinical data and experiments about the pathophysiology of these arterial occlusive events with BCR-ABL TKIs. Imatinib is associated with very low rates of thrombosis, suggesting a potentially protecting cardiovascular effect of this treatment in patients with BCR-ABL CML. This protective effect might be mediated by decreased platelet secretion and activation, decreased leukocyte recruitment, and anti-inflammatory or antifibrotic effects. Clinical data have guided mechanistic studies toward alteration of platelet functions and atherosclerosis development, which might be secondary to metabolism impairment. Dasatinib, nilotinib, and ponatinib affect endothelial cells and might induce atherogenesis through increased vascular permeability. Nilotinib also impairs platelet functions and induces hyperglycemia and dyslipidemia that might contribute to atherosclerosis development. Description of the pathophysiology of arterial thrombotic events is necessary to implement risk minimization strategies.

Keywords

BCR-ABL - arterial thrombotic events - tyrosine kinase inhibitors - chronic myeloid leukemia

• References

• 1 Bhamidipati PK, Kantarjian H, Cortes J, Cornelison AM, Jabbour E. Management of imatinib-resistant patients with chronic myeloid leukemia. Ther Adv Hematol 2013; 4 (02) 103-117
• 2 Gorre ME, Mohammed M, Ellwood K. , et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293 (5531): 876-880
• 3 Bixby D, Talpaz M. Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance. Hematology (Am Soc Hematol Educ Program) 2009; 2009 (01) 461-476
• 4 Cortes JE, Saglio G, Kantarjian HM. , et al. Final 5-year study results of DASISION: the Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol 2016; 34 (20) 2333-2340
• 5 Hochhaus A, Saglio G, Hughes TP. , et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 2016; 30 (05) 1044-1054
• 6 Brümmendorf TH, Cortes JE, de Souza CA. , et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol 2015; 168 (01) 69-81
• 7 Mealing S, Barcena L, Hawkins N. , et al. The relative efficacy of imatinib, dasatinib and nilotinib for newly diagnosed chronic myeloid leukemia: a systematic review and network meta-analysis. Exp Hematol Oncol 2013; 2 (01) 5
• 8 Lamontanara AJ, Gencer EB, Kuzyk O, Hantschel O. Mechanisms of resistance to BCR-ABL and other kinase inhibitors. Biochim Biophys Acta 2013; 1834 (07) 1449-1459
• 9 Pagnano KB, Bendit I, Boquimpani C. , et al; Latin American Leukemia Net (LALNET). BCR-ABL mutations in chronic myeloid leukemia treated with tyrosine kinase inhibitors and impact on survival. Cancer Invest 2015; 33 (09) 451-458
• 10 Ursan ID, Jiang R, Pickard EM, Lee TA, Ng D, Pickard AS. Emergence of BCR-ABL kinase domain mutations associated with newly diagnosed chronic myeloid leukemia: a meta-analysis of clinical trials of tyrosine kinase inhibitors. J Manag Care Spec Pharm 2015; 21 (02) 114-122
• 11 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia. Version 1.2017. 2016
• 12 Thanopoulou E, Judson I. The safety profile of imatinib in CML and GIST: long-term considerations. Arch Toxicol 2012; 86 (01) 1-12
• 13 Kalmanti L, Saussele S, Lauseker M. , et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia 2015; 29 (05) 1123-1132
• 14 Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol 2015; 33 (35) 4210-4218
• 15 Breccia M, Alimena G. Pleural/pericardic effusions during dasatinib treatment: incidence, management and risk factors associated to their development. Expert Opin Drug Saf 2010; 9 (05) 713-721
• 16 European Medicines Agency. Sprycel - Summary of Product Characteristics 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000709/WC500056998.pdf . Accessed December 22, 2017
• 17 European Medicines Agency. Iclusig - Summary of Product Characteristics 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002695/WC500145646.pdf . Accessed December 22, 2017
• 18 European Medicines Agency. Tasigna - Summary of Product Characteristics 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000798/WC500034394.pdf . Accessed December 22, 2017
• 19 Kantarjian HM, Cortes JE, Kim DW. , et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood 2014; 123 (09) 1309-1318
• 20 Saglio G, Kim D-W, Issaragrisil S. , et al; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362 (24) 2251-2259
• 21 Poch Martell M, Sibai H, Deotare U, Lipton JH. Ponatinib in the therapy of chronic myeloid leukemia. Expert Rev Hematol 2016; 9 (10) 923-932
• 22 Douxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogné JM. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: a systematic review and meta-analysis. JAMA Oncol 2016;
• 23 Haguet H, Douxfils J, Mullier F, Chatelain C, Graux C, Dogné JM. Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis. Expert Opin Drug Saf 2017; 16 (01) 5-12
• 24 Cortes J, Kim D-W, Pinilla-Ibarz J. , et al. Ponatinib efficacy and safety in heavily pretreated leukemia patients: 3-year results of the PACE trial. 20th Congress of EHA; Copenhagen, Denmark, June 12, 2015
• 25 Pasvolsky O, Leader A, Iakobishvili Z, Wasserstrum Y, Kornowski R, Raanani P. Tyrosine kinase inhibitor associated vascular toxicity in chronic myeloid leukemia. Cardio-Oncology 2015; 1 (01) 5
• 26 Gora-Tybor J, Medras E, Calbecka M. , et al. Real-life comparison of severe vascular events and other non-hematological complications in patients with chronic myeloid leukemia undergoing second-line nilotinib or dasatinib treatment. Leuk Lymphoma 2015; 56 (08) 2309-2314
• 27 le Coutre PD, Hughes TP, Mahon FX. , et al. Low incidence of peripheral arterial disease in patients receiving dasatinib in clinical trials. Leukemia 2016; 30 (07) 1593-1596
• 28 Sam PY, Ahaneku H, Nogueras-Gonzalez GM. , et al. Cardiovascular events among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Blood 2016; 128 (22) 1919
• 29 Lassila M, Allen TJ, Cao Z. , et al. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24 (05) 935-942
• 30 Ma LK, Li Q, He LF. , et al. Imatinib attenuates myocardial fibrosis in association with inhibition of the PDGFRα activity. Arq Bras Cardiol 2012; 99 (06) 1082-1091
• 31 Fossard G, Blond E, Balsat M. , et al. Hyperhomocysteinemia and high doses of nilotinib favor cardiovascular events in chronic phase chronic myelogenous leukemia patients. Haematologica 2016; 101 (03) e86-e90
• 32 Kostos L, Burbury K, Srivastava G, Prince HM. Gastrointestinal bleeding in a chronic myeloid leukaemia patient precipitated by dasatinib-induced platelet dysfunction: case report. Platelets 2015; 26 (08) 809-811
• 33 Mazharian A, Ghevaert C, Zhang L, Massberg S, Watson SP. Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation. Blood 2011; 117 (19) 5198-5206
• 34 Alhawiti N, Burbury KL, Kwa FA. , et al. The tyrosine kinase inhibitor, nilotinib potentiates a prothrombotic state. Thromb Res 2016; 145: 54-64
• 35 Lotfi K, Deb S, Sjöström C, Tharmakulanathan A, Boknäs N, Ramström S. Individual variation in hemostatic alterations caused by tyrosine kinase inhibitors: a way to improve personalized cancer therapy?. Blood 2016; 128 (22) 1908
• 36 Li R, Grosser T, Diamond SL. Microfluidic whole blood testing of platelet response to pharmacological agents. Platelets 2017; 28 (05) 457-462
• 37 Senis YA, Mazharian A, Mori J. Src family kinases: at the forefront of platelet activation. Blood 2014; 124 (13) 2013-2024
• 38 Gratacap MP, Martin V, Valéra MC. , et al. The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo. Blood 2009; 114 (09) 1884-1892
• 39 Albrecht-Schgoer K, Huber K, Grebien F. , et al. Nilotinib exerts direct pro-atherogenic and anti-angiogenic effects on vascular endothelial cells: a potential explanation for drug-induced vasculopathy in CML. Blood 2013; 122 (21) 257
• 40 Shimabukuro-Vornhagen A, Rothe A, Nogova L, Kochanek M, Scheid C, von Bergwelt-Baildon M. Improvement of platelet dysfunction in chronic myelogenous leukemia following treatment with imatinib: a case report. J Med Case Reports 2011; 5: 215
• 41 Neelakantan P, Marin D, Laffan M, Goldman J, Apperley J, Milojkovic D. Platelet dysfunction associated with ponatinib, a new pan BCR-ABL inhibitor with efficacy for chronic myeloid leukemia resistant to multiple tyrosine kinase inhibitor therapy. Haematologica 2012; 97 (09) 1444
• 42 Loren CP, Aslan JE, Rigg RA. , et al. The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling, platelet activation and aggregate formation under shear. Thromb Res 2015; 135 (01) 155-160
• 43 Rivera VM, Pritchard JR, Gonzalvez F, Baker T, Gozgit JM, Hodgson G. Comparative TKI profiling analyses to explore potential mechanisms of Ponatinib-associated arterial thrombotic events. Blood 2014; 124 (21) 1783
• 44 Quintás-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009; 114 (02) 261-263
• 45 Breccia M, Muscaritoli M, Aversa Z, Mandelli F, Alimena G. Imatinib mesylate may improve fasting blood glucose in diabetic Ph+ chronic myelogenous leukemia patients responsive to treatment. J Clin Oncol 2004; 22 (22) 4653-4655
• 46 Breccia M, Alimena G. The metabolic consequences of imatinib mesylate: changes on glucose, lypidic and bone metabolism. Leuk Res 2009; 33 (07) 871-875
• 47 Agostino NM, Chinchilli VM, Lynch CJ. , et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice. J Oncol Pharm Pract 2011; 17 (03) 197-202
• 48 Breccia M, Muscaritoli M, Cannella L, Stefanizzi C, Frustaci A, Alimena G. Fasting glucose improvement under dasatinib treatment in an accelerated phase chronic myeloid leukemia patient unresponsive to imatinib and nilotinib. Leuk Res 2008; 32 (10) 1626-1628
• 49 Ono K, Suzushima H, Watanabe Y. , et al. Rapid amelioration of hyperglycemia facilitated by dasatinib in a chronic myeloid leukemia patient with type 2 diabetes mellitus. Intern Med 2012; 51 (19) 2763-2766
• 50 Louvet C, Szot GL, Lang J. , et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A 2008; 105 (48) 18895-18900
• 51 Hägerkvist R, Jansson L, Welsh N. Imatinib mesylate improves insulin sensitivity and glucose disposal rates in rats fed a high-fat diet. Clin Sci (Lond) 2008; 114 (01) 65-71
• 52 Han MS, Chung KW, Cheon HG. , et al. Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice. Diabetes 2009; 58 (02) 329-336
• 53 Hägerkvist R, Makeeva N, Elliman S, Welsh N. Imatinib mesylate (Gleevec) protects against streptozotocin-induced diabetes and islet cell death in vitro. Cell Biol Int 2006; 30 (12) 1013-1017
• 54 Hägerkvist R, Sandler S, Mokhtari D, Welsh N. Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning. FASEB J 2007; 21 (02) 618-628
• 55 Xia CQ, Zhang P, Li S. , et al. C-Abl inhibitor imatinib enhances insulin production by β cells: c-Abl negatively regulates insulin production via interfering with the expression of NKx2.2 and GLUT-2. PLoS One 2014; 9 (05) e97694
• 56 Sadiq S, Owen E, Foster T. , et al. Nilotinib-induced metabolic dysfunction: insights from a translational pilot study using in vitro adipocyte models and patient cohorts. 22nd EHA congress; June 22–25, 2017; Madrid, Spain
• 57 Iizuka K, Niwa H, Kato T, Takeda J. Dasatinib improves insulin sensitivity and affects lipid metabolism in a patient with chronic myeloid leukaemia. BMJ Case Rep 2016; 2016: 201
• 58 Fitter S, Vandyke K, Schultz CG, White D, Hughes TP, Zannettino AC. Plasma adiponectin levels are markedly elevated in imatinib-treated chronic myeloid leukemia (CML) patients: a mechanism for improved insulin sensitivity in type 2 diabetic CML patients?. J Clin Endocrinol Metab 2010; 95 (08) 3763-3767
• 59 Hosch SE, Olefsky JM, Kim JJ. APPLied mechanics: uncovering how adiponectin modulates insulin action. Cell Metab 2006; 4 (01) 5-6
• 60 Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity. Obes Rev 2005; 6 (01) 13-21
• 61 Fitter S, Vandyke K, Gronthos S, Zannettino AC. Suppression of PDGF-induced PI3 kinase activity by imatinib promotes adipogenesis and adiponectin secretion. J Mol Endocrinol 2012; 48 (03) 229-240
• 62 Aichberger KJ, Herndlhofer S, Schernthaner GH. , et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol 2011; 86 (07) 533-539
• 63 Breccia M, Muscaritoli M, Gentilini F. , et al. Impaired fasting glucose level as metabolic side effect of nilotinib in non-diabetic chronic myeloid leukemia patients resistant to imatinib. Leuk Res 2007; 31 (12) 1770-1772
• 64 Castagnetti F, Breccia M, Gugliotta G. , et al; GIMEMA CML Working Party. Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients. Haematologica 2016; 101 (10) 1200-1207
• 65 Delphine R, Gautier J-f, Breccia M. , et al. Incidence of hyperglycemia by 3 years in patients (Pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with Nilotinib (NIL) or Imatinib (IM) in ENESTnd. Blood 2012; 120 (21) 1686
• 66 Iurlo A, Orsi E, Cattaneo D. , et al. Effects of first- and second-generation tyrosine kinase inhibitor therapy on glucose and lipid metabolism in chronic myeloid leukemia patients: a real clinical problem?. Oncotarget 2015; 6 (32) 33944-33951
• 67 Racil Z, Razga F, Drapalova J. , et al. Mechanism of impaired glucose metabolism during nilotinib therapy in patients with chronic myelogenous leukemia. Haematologica 2013; 98 (10) e124-e126
• 68 Ito Y, Miyamoto T, Chong Y, Maki T, Akashi K, Kamimura T. Nilotinib exacerbates diabetes mellitus by decreasing secretion of endogenous insulin. Int J Hematol 2013; 97 (01) 135-138
• 69 Hadzijusufovic E, Herndlhofer S, Aichberger KJ. , et al. Nilotinib exerts direct effects on vascular endothelial cells and may act as a co-trigger of atherosclerosis in patients with Ph+ CML. Blood 2011; 118 (21) 2753
• 70 Breccia M, Loglisci G, Salaroli A, Serrao A, Alimena G. Nilotinib-mediated increase in fasting glucose level is reversible, does not convert to type 2 diabetes and is likely correlated with increased body mass index. Leuk Res 2012; 36 (04) e66-e67
• 71 Saglio G, Larson RA, Hughes TP. , et al. Efficacy and safety of Nilotinib in chronic phase (CP) chronic myeloid leukemia (CML) patients (Pts) with type 2 diabetes in the ENESTnd trial. Blood 2010; 116 (21) 3430
• 72 Frasca F, Pandini G, Malaguarnera R. , et al. Role of c-Abl in directing metabolic versus mitogenic effects in insulin receptor signaling. J Biol Chem 2007; 282 (36) 26077-26088
• 73 Franceschino A, Tornaghi L, Benemacher V, Assouline S, Gambacorti-Passerini C. Alterations in creatine kinase, phosphate and lipid values in patients with chronic myeloid leukemia during treatment with imatinib. Haematologica 2008; 93 (02) 317-318
• 74 Gottardi M, Manzato E, Gherlinzoni F. Imatinib and hyperlipidemia. N Engl J Med 2005; 353 (25) 2722-2723
• 75 Gologan R, Constantinescu G, Georgescu D. , et al. Hypolipemiant besides antileukemic effect of imatinib mesylate. Leuk Res 2009; 33 (09) 1285-1287
• 76 Ellis M, Krashin E, Hamburger-Avnery O, Gan S, Elis A, Ashur-Fabian O. The anti-leukemic and lipid lowering effects of imatinib are not hindered by statins in CML: a retrospective clinical study and in vitro assessment of lipid-genes transcription. Leuk Lymphoma 2017; 58 (05) 1172-1177
• 77 Franklin M, Burns L, Perez S, Yerragolam D, Makenbaeva D. Incidence of type II diabetes mellitus and hyperlipidemia in patients prescribed Dasatinib or Nilotinib as first or second line therapy for chronic myelogenous leukemia (CML). Blood 2016; 128 (22) 4766
• 78 Rea D, Mirault T, Cluzeau T. , et al. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia. Haematologica 2014; 99 (07) 1197-1203
• 79 Maurizot A, Beressi JP, Manéglier B. , et al. Rapid clinical improvement of peripheral artery occlusive disease symptoms after nilotinib discontinuation despite persisting vascular occlusion. Blood Cancer J 2014; 4: e247
• 80 Breccia M, Molica M, Alimena G. How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. Leuk Res 2014; 38 (12) 1392-1398
• 81 Venalis P, Maurer B, Akhmetshina A. , et al. Lack of inhibitory effects of the anti-fibrotic drug imatinib on endothelial cell functions in vitro and in vivo. J Cell Mol Med 2009; 13 (10) 4185-4191
• 82 Gover-Proaktor A, Granot G, Shapira S. , et al. Ponatinib reduces viability, migration, and functionality of human endothelial cells. Leuk Lymphoma 2017; 58 (06) 1455-1467
• 83 Vallières K, Petitclerc E, Laroche G. On the ability of imatinib mesylate to inhibit smooth muscle cell proliferation without delaying endothelialization: an in vitro study. Vascul Pharmacol 2009; 51 (01) 50-56
• 84 Hacker TA, Griffin MO, Guttormsen B, Stoker S, Wolff MR. Platelet-derived growth factor receptor antagonist STI571 (imatinib mesylate) inhibits human vascular smooth muscle proliferation and migration in vitro but not in vivo. J Invasive Cardiol 2007; 19 (06) 269-274
• 85 Vrekoussis T, Stathopoulos EN, De Giorgi U. , et al. Modulation of vascular endothelium by imatinib: a study on the EA.hy 926 endothelial cell line. J Chemother 2006; 18 (01) 56-65
• 86 Letsiou E, Rizzo AN, Sammani S. , et al. Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2015; 308 (03) L259-L269
• 87 Guignabert C, Phan C, Seferian A. , et al. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. J Clin Invest 2016; 126 (09) 3207-3218
• 88 Rizzo AN, Sammani S, Esquinca AE. , et al. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2015; 309 (11) L1294-L1304
• 89 Katgı A, Sevindik ÖG, Gökbulut AA. , et al. Nilotinib does not alter the secretory functions of carotid artery endothelial cells in a prothrombotic or antithrombotic fashion. Clin Appl Thromb Hemost 2015; 21 (07) 678-683
• 90 Hadzijusufovic E, Kirchmair R, Theurl M. , et al. Ponatinib exerts multiple effects on vascular endothelial cells: possible mechanisms and explanations for the adverse vascular events seen in CML patients treated with Ponatinib. Blood 2016; 128 (22) 1883
• 91 Lorenzi M, Cagliero E, Toledo S. Glucose toxicity for human endothelial cells in culture. Delayed replication, disturbed cell cycle, and accelerated death. Diabetes 1985; 34 (07) 621-627
• 92 Shah NP, Wallis N, Farber HW. , et al. Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol 2015; 90 (11) 1060-1064
• 93 Frost AE, Barst RJ, Hoeper MM. , et al. Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. J Heart Lung Transplant 2015; 34 (11) 1366-1375
• 94 Dasgupta SK, Le A, Vijayan KV, Thiagarajan P. Dasatinib inhibits actin fiber reorganization and promotes endothelial cell permeability through RhoA-ROCK pathway. Cancer Med 2017; 6 (04) 809-818
• 95 Dewar AL, Domaschenz RM, Doherty KV, Hughes TP, Lyons AB. Imatinib inhibits the in vitro development of the monocyte/macrophage lineage from normal human bone marrow progenitors. Leukemia 2003; 17 (09) 1713-1721
• 96 Brownlow N, Mol C, Hayford C, Ghaem-Maghami S, Dibb NJ. Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor. Leukemia 2009; 23 (03) 590-594
• 97 Dewar AL, Doherty KV, Hughes TP, Lyons AB. Imatinib inhibits the functional capacity of cultured human monocytes. Immunol Cell Biol 2005; 83 (01) 48-56
• 98 Dewar AL, Cambareri AC, Zannettino ACW. , et al. Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood 2005; 105 (08) 3127-3132
• 99 Metharom P, Martin K, Kumar AH. , et al. Pleiotropic role for monocyte C-fms protein in response to vascular injury: potential therapeutic target. Atherosclerosis 2011; 216 (01) 74-82
• 100 Gacic J, Vorkapic E, Olsen RS. , et al. Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages. Pharmacol Rep 2016; 68 (01) 1-6
• 101 Cwynarski K, Laylor R, Macchiarulo E. , et al. Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. Leukemia 2004; 18 (08) 1332-1339
• 102 Brownlow N, Russell AE, Saravanapavan H. , et al. Comparison of nilotinib and imatinib inhibition of FMS receptor signaling, macrophage production and osteoclastogenesis. Leukemia 2008; 22 (03) 649-652
• 103 Ozanne J, Prescott AR, Clark K. The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases. Biochem J 2015; 465 (02) 271-279
• 104 Darling NJ, Toth R, Arthur JS, Clark K. Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages. Biochem J 2017; 474 (04) 521-537
• 105 Schade AE, Schieven GL, Townsend R. , et al. Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood 2008; 111 (03) 1366-1377
• 106 Blake SJ, Lyons AB, Hughes TP. Nilotinib inhibits the Src-family kinase LCK and T-cell function in vitro. J Cell Mol Med 2009; 13 (03) 599-601
• 107 Blake S, Hughes TP, Mayrhofer G, Lyons AB. The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro. Clin Immunol 2008; 127 (03) 330-339
• 108 Lee KC, Ouwehand I, Giannini AL, Thomas NS, Dibb NJ, Bijlmakers MJ. Lck is a key target of imatinib and dasatinib in T-cell activation. Leukemia 2010; 24 (04) 896-900
• 109 Farha S, Dweik R, Rahaghi F. , et al. Imatinib in pulmonary arterial hypertension: c-Kit inhibition. Pulm Circ 2014; 4 (03) 452-455
• 110 Juurikivi A, Sandler C, Lindstedt KA. , et al. Inhibition of c-kit tyrosine kinase by imatinib mesylate induces apoptosis in mast cells in rheumatoid synovia: a potential approach to the treatment of arthritis. Ann Rheum Dis 2005; 64 (08) 1126-1131
• 111 Sun YL, Kumar P, Sodani K. , et al. Ponatinib enhances anticancer drug sensitivity in MRP7-overexpressing cells. Oncol Rep 2014; 31 (04) 1605-1612
• 112 Yvan-Charvet L, Wang N, Tall AR. Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler Thromb Vasc Biol 2010; 30 (02) 139-143
• 113 Chen Z, Lee FY, Bhalla KN, Wu J. Potent inhibition of platelet-derived growth factor-induced responses in vascular smooth muscle cells by BMS-354825 (dasatinib). Mol Pharmacol 2006; 69 (05) 1527-1533
• 114 Nakamura K, Akagi S, Ogawa A. , et al. Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Int J Cardiol 2012; 159 (02) 100-106
• 115 Li L, Blumenthal DK, Masaki T, Terry CM, Cheung AK. Differential effects of imatinib on PDGF-induced proliferation and PDGF receptor signaling in human arterial and venous smooth muscle cells. J Cell Biochem 2006; 99 (06) 1553-1563
• 116 Rocha A, Azevedo I, Soares R. Anti-angiogenic effects of imatinib target smooth muscle cells but not endothelial cells. Angiogenesis 2007; 10 (04) 279-286
• 117 Ballinger ML, Osman N, Hashimura K. , et al. Imatinib inhibits vascular smooth muscle proteoglycan synthesis and reduces LDL binding in vitro and aortic lipid deposition in vivo. J Cell Mol Med 2010; 14 (6B): 1408-1418
• 118 Distler JH, Jüngel A, Huber LC. , et al. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 2007; 56 (01) 311-322
• 119 Yoshiji H, Noguchi R, Kuriyama S. , et al. Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol 2005; 288 (05) G907-G913
• 120 Salhotra A, Tsai N, Thomas SH. , et al. Sclerodermatous chronic GVHD in patients receiving tyrosine kinase inhibitors after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2015; 50 (01) 139-141
• 121 Makiyama Y, Toba K, Kato K. , et al. Imatinib mesilate inhibits neointimal hyperplasia via growth inhibition of vascular smooth muscle cells in a rat model of balloon injury. Tohoku J Exp Med 2008; 215 (04) 299-306
• 122 Park D, Kim SM, Min SI, Ha J, Kim IG, Min SK. Inhibition of intimal hyperplasia by local perivascular application of rapamycin and imatinib mesilate after carotid balloon injury. J Korean Surg Soc 2013; 85 (06) 296-301
• 123 Leppänen O, Rutanen J, Hiltunen MO. , et al. Oral imatinib mesylate (STI571/Gleevec) improves the efficacy of local intravascular vascular endothelial growth factor-C gene transfer in reducing neointimal growth in hypercholesterolemic rabbits. Circulation 2004; 109 (09) 1140-1146
• 124 Sevim KZ, Silistreli O, Gorgu M, Sevim O, Ergur B. Short-term vasculoprotective effects of imatinib mesylate on intimal hyperplasia of arterial anastomosis: An experimental study using a rabbit model. Can J Plast Surg 2012; 20 (04) 223-228
• 125 Wu J, Chen Z, Bhalla KN. Treatment of restenosis and stenosis with dasatinib (2014). USF Patents. 152
• 126 Sánchez-Ortega I, Servitje O, Arnan M. , et al. Dasatinib as salvage therapy for steroid refractory and imatinib resistant or intolerant sclerotic chronic graft-versus-host disease. Biol Blood Marrow Transplant 2012; 18 (02) 318-323
• 127 Marinelli Busilacchi E, Olivieri J, Viola N. , et al. The exaggerated collagen expression in Gvhd-fibroblasts is effectively inhibited by therapeutic concentration of Nilotinib. Blood 2016; 128 (22) 4597
• 128 Shiha GE, Abu-Elsaad NM, Zalata KR, Ibrahim TM. Tracking anti-fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: an insight. Clin Exp Pharmacol Physiol 2014; 41 (10) 788-797
• 129 Giles FJ, O'Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia 2009; 23 (10) 1698-1707
• 130 Rix U, Hantschel O, Dürnberger G. , et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 2007; 110 (12) 4055-4063
• 131 Pardanani A, Tefferi A. Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Blood 2004; 104 (07) 1931-1939
• 132 Bantscheff M, Eberhard D, Abraham Y. , et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol 2007; 25 (09) 1035-1044
• 133 Weisberg E, Manley PW, Breitenstein W. , et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7 (02) 129-141
• 134 Buchdunger E, Cioffi CL, Law N. , et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000; 295 (01) 139-145
• 135 Manley PW, Drueckes P, Fendrich G. , et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta 2010; 1804 (03) 445-453
• 136 Fabian MA, Biggs III WH, Treiber DK. , et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005; 23 (03) 329-336
• 137 Shi H, Zhang CJ, Chen GY, Yao SQ. Cell-based proteome profiling of potential dasatinib targets by use of affinity-based probes. J Am Chem Soc 2012; 134 (06) 3001-3014
• 138 Liu Y, Wang Z, Kwong SQ. , et al. Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib. J Hepatol 2011; 55 (03) 612-625
• 139 Sakamoto A, Sugamoto Y, Tokunaga Y. , et al. Expression profiling of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. J Int Med Res 2011; 39 (02) 522-527
• 140 Khan AA, Sandhya VK, Singh P. , et al. Signaling network map of endothelial TEK tyrosine kinase. J Signal Transduct 2014; 2014: 173026
• 141 Chislock EM, Ring C, Pendergast AM. Abl kinases are required for vascular function, Tie2 expression, and angiopoietin-1-mediated survival. Proc Natl Acad Sci U S A 2013; 110 (30) 12432-12437
• 142 Boulanger CM, Loyer X, Rautou PE, Amabile N. Extracellular vesicles in coronary artery disease. Nat Rev Cardiol 2017; 14 (05) 259-272
• 143 Aghel N, Delgado DH, Lipton JH. Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: preventive strategies and cardiovascular surveillance. Vasc Health Risk Manag 2017; 13: 293-303
• 144 Damrongwatanasuk R, Fradley MG. Cardiovascular complications of targeted therapies for chronic myeloid leukemia. Curr Treat Options Cardiovasc Med 2017; 19 (04) 24
• 145 Valent P, Hadzijusufovic E, Hoermann G. , et al. Risk factors and mechanisms contributing to TKI-induced vascular events in patients with CML. Leuk Res 2017; 59: 47-54
• 146 García-Gutiérrez V, Jiménez-Velasco A, Gómez-Casares MT, Sánchez-Guijo F, López-Sendón JL, Steegmann Olmedillas JL. [Cardiovascular management of patients with chronic myeloid leukemia from a multidisciplinary perspective, and proposing action protocol by consensus meeting]. Med Clin (Barc) 2016; 146 (12) 561.e1-561.e8
• 147 Aman J, van Bezu J, Damanafshan A. , et al. Effective treatment of edema and endothelial barrier dysfunction with imatinib. Circulation 2012; 126 (23) 2728-2738
• 148 Kim SR, Suh W. Beneficial effects of the Src inhibitor, dasatinib, on breakdown of the blood-retinal barrier. Arch Pharm Res 2017; 40 (02) 197-203
• 149 Sukegawa M, Wang X, Nishioka C. , et al. The BCR/ABL tyrosine kinase inhibitor, nilotinib, stimulates expression of IL-1β in vascular endothelium in association with downregulation of miR-3p. Leuk Res 2017; 58: 83-90
• 150 Wolf AM, Wolf D, Rumpold H. , et al. The kinase inhibitor imatinib mesylate inhibits TNF-alpha production in vitro and prevents TNF-dependent acute hepatic inflammation. Proc Natl Acad Sci U S A 2005; 102 (38) 13622-13627
• 151 Fraser CK, Lousberg EL, Kumar R, Hughes TP, Diener KR, Hayball JD. Dasatinib inhibits the secretion of TNF-alpha following TLR stimulation in vitro and in vivo. Exp Hematol 2009; 37 (12) 1435-1444
• 152 Seggewiss R, Loré K, Greiner E. , et al. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 2005; 105 (06) 2473-2479
• 153 Dietz AB, Souan L, Knutson GJ, Bulur PA, Litzow MR, Vuk-Pavlovic S. Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood 2004; 104 (04) 1094-1099
• 154 Chen J, Schmitt A, Chen B. , et al. Nilotinib hampers the proliferation and function of CD8+ T lymphocytes through inhibition of T cell receptor signalling. J Cell Mol Med 2008; 12 (5B): 2107-2118
• 155 Perros F, Montani D, Dorfmüller P. , et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2008; 178 (01) 81-88
• 156 Canning P, Tan L, Chu K, Lee SW, Gray NS, Bullock AN. Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors. J Mol Biol 2014; 426 (13) 2457-2470
• 157 Hantschel O, Rix U, Superti-Furga G. Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma 2008; 49 (04) 615-619
• 158 Remsing Rix LL, Rix U, Colinge J. , et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia 2009; 23 (03) 477-485
• 159 Green MR, Newton MD, Fancher KM. Off-Target Effects of BCR-ABL and JAK2 Inhibitors. Am J Clin Oncol 2016; 39 (01) 76-84