Tyrosine Kinase Inhibitors in Pulmonary Arterial Hypertension: A Double-Edge Sword?

Laurent Godinas; Christophe Guignabert; Andrei Seferian; Frederic Perros; Emmanuel Bergot; Yves Sibille; Marc Humbert; David Montani

doi:10.1055/s-0033-1356494

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med 2013; 34(05): 714-724
DOI: 10.1055/s-0033-1356494

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Tyrosine Kinase Inhibitors in Pulmonary Arterial Hypertension: A Double-Edge Sword?

Laurent Godinas

¹Pulmonary Section, Cliniques Universitaires de Mont-Godinne, University of Louvain, Yvoir, Belgium

,

Christophe Guignabert

²University Paris-Sud, Le Kremlin-Bicêtre, France

³AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

⁴INSERM U999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France

,

Andrei Seferian

²University Paris-Sud, Le Kremlin-Bicêtre, France

³AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

⁴INSERM U999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France

,

Frederic Perros

²University Paris-Sud, Le Kremlin-Bicêtre, France

³AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

⁴INSERM U999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France

,

Emmanuel Bergot

⁵Centre Hospitalier Universitaire de Caen, Service de Pneumologie et Centre Régional de Compétence de l'HTAP, Caen, France

⁶ER3 INSERM, Université de Caen, Caen, France

,

Yves Sibille

¹Pulmonary Section, Cliniques Universitaires de Mont-Godinne, University of Louvain, Yvoir, Belgium

,

Marc Humbert

²University Paris-Sud, Le Kremlin-Bicêtre, France

³AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

⁴INSERM U999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France

,

David Montani

²University Paris-Sud, Le Kremlin-Bicêtre, France

³AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

⁴INSERM U999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France

› Author Affiliations

Abstract

New treatments for pulmonary arterial hypertension (PAH) are a crucial need. The increased proliferation, migration, and survival of pulmonary vascular cells within the pulmonary artery wall in PAH have allowed successful transposition of pathophysiological elements from oncologic researches. Next steps will require translation of these biological advances in PAH therapeutic arsenal and guidelines. This review synthesizes recent data concerning the role of receptor tyrosine kinases and their inhibitors in PAH, with implications in animal models and humans. Results of clinical trials are now accumulating to establish beneficial role of tyrosine kinase inhibitors (TKIs) in PAH and further findings are expected in the near future. Beside this curative approach, evidences of a possible TKI-induced cardiotoxicity are emerging. These safety issues raise concern about a potential amplified harmful effect in PAH, a pathology characterized by an underlying cardiac dysfunction. In addition, analyses of PAH registries shed light on a selective pulmonary vascular toxicity triggered by TKIs, especially dasatinib. These possible dual effects of the TKIs in PAH need to be taken in account for future pharmacological development of this therapeutic class in PAH.

Keywords

pulmonary arterial hypertension - receptor tyrosine kinase - imatinib - sorafenib - dasatinib - cardiotoxicity

Full Text

References

References
1 Humbert M, Morrell NW, Archer SL , et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43 (12, Suppl S ): 13S-24S
2 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351 (14) 1425-1436
3 Galiè N, Hoeper MM, Humbert M , et al; Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34 (6) 1219-1263
4 Rai PR, Cool CD, King JA , et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2008; 178 (6) 558-564
5 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100 (1) 57-70
6 Sakao S, Tatsumi K. Vascular remodeling in pulmonary arterial hypertension: multiple cancer-like pathways and possible treatment modalities. Int J Cardiol 2011; 147 (1) 4-12
7 Tu L, Dewachter L, Gore B , et al. Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension. Am J Respir Cell Mol Biol 2011; 45 (2) 311-322
8 Tu L, De Man FS, Girerd B , et al. A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents. Am J Respir Crit Care Med 2012; 186 (7) 666-676
9 Masri FA, Xu W, Comhair SA , et al. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007; 293 (3) L548-L554
10 Geraci MW, Moore M, Gesell T , et al. Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ Res 2001; 88 (6) 555-562
11 Lévy M, Maurey C, Celermajer DS , et al. Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease. J Am Coll Cardiol 2007; 49 (7) 803-810
12 Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF. The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 2001; 22 (3) 405-418
13 Tuder RM, Chacon M, Alger L , et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol 2001; 195 (3) 367-374
14 Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998; 101 (5) 927-934
15 Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 2001; 88 (1) E2-E11
16 Montani D, Perros F, Gambaryan N , et al. C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2011; 184 (1) 116-123
17 Stenmark KR, Frid MG, Yeager M , et al. Targeting the adventitial microenvironment in pulmonary hypertension: A potential approach to therapy that considers epigenetic change. Pulm Circ 2012; 2 (1) 3-14
18 Davie NJ, Crossno Jr JT, Frid MG , et al. Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol 2004; 286 (4) L668-L678
19 Gerasimovskaya EV, Woodward HN, Tucker DA, Stenmark KR. Extracellular ATP is a pro-angiogenic factor for pulmonary artery vasa vasorum endothelial cells. Angiogenesis 2008; 11 (2) 169-182
20 Xu W, Koeck T, Lara AR , et al. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci U S A 2007; 104 (4) 1342-1347
21 Sakao S, Taraseviciene-Stewart L, Cool CD , et al. VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD34+ precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells. FASEB J 2007; 21 (13) 3640-3652
22 Sakao S, Tatsumi K, Voelkel NF. Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation. Respir Res 2009; 10: 95
23 Sakao S, Tatsumi K, Voelkel NF. Reversible or irreversible remodeling in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2010; 43 (6) 629-634
24 Adnot S. Lessons learned from cancer may help in the treatment of pulmonary hypertension. J Clin Invest 2005; 115 (6) 1461-1463
25 de Man FS, Tu L, Handoko ML , et al. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186 (8) 780-789
26 Guignabert C, Tu L, Izikki M , et al. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. FASEB J 2009; 23 (12) 4135-4147
27 McMurtry MS, Archer SL, Altieri DC , et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005; 115 (6) 1479-1491
28 Davies RJ, Holmes AM, Deighton J , et al. BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol Lung Cell Mol Physiol 2012; 302 (6) L604-L615
29 Zhang S, Fantozzi I, Tigno DD , et al. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2003; 285 (3) L740-L754
30 Jeffery TK, Wanstall JC. Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension. Pharmacol Ther 2001; 92 (1) 1-20
31 Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 2006; 99 (7) 675-691
32 Das M, Dempsey EC, Reeves JT, Stenmark KR. Selective expansion of fibroblast subpopulations from pulmonary artery adventitia in response to hypoxia. Am J Physiol Lung Cell Mol Physiol 2002; 282 (5) L976-L986
33 Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev 2004; 15 (4) 197-204
34 Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 1999; 79 (4) 1283-1316
35 Claesson-Welsh L. Platelet-derived growth factor receptor signals. J Biol Chem 1994; 269 (51) 32023-32026
36 Grimminger F, Schermuly RT. PDGF receptor and its antagonists: role in treatment of PAH. Adv Exp Med Biol 2010; 661: 435-446
37 Balasubramaniam V, Le Cras TD, Ivy DD, Grover TR, Kinsella JP, Abman SH. Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 2003; 284 (5) L826-L833
38 Jankov RP, Kantores C, Belcastro R , et al. A role for platelet-derived growth factor beta-receptor in a newborn rat model of endothelin-mediated pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 2005; 288 (6) L1162-L1170
39 Humbert M, Monti G, Fartoukh M , et al. Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur Respir J 1998; 11 (3) 554-559
40 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 (1) 81-88
41 Wedgwood S, Devol JM, Grobe A , et al. Fibroblast growth factor-2 expression is altered in lambs with increased pulmonary blood flow and pulmonary hypertension. Pediatr Res 2007; 61 (1) 32-36
42 Arcot SS, Fagerland JA, Lipke DW, Gillespie MN, Olson JW. Basic fibroblast growth factor alterations during development of monocrotaline-induced pulmonary hypertension in rats. Growth Factors 1995; 12 (2) 121-130
43 Benisty JI, McLaughlin VV, Landzberg MJ , et al. Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 2004; 126 (4) 1255-1261
44 Izikki M, Guignabert C, Fadel E , et al. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 2009; 119 (3) 512-523
45 Normanno N, Bianco C, De Luca A, Salomon DS. The role of EGF-related peptides in tumor growth. Front Biosci 2001; 6: D685-D707
46 Holsinger FC, Doan DD, Jasser SA , et al. Epidermal growth factor receptor blockade potentiates apoptosis mediated by Paclitaxel and leads to prolonged survival in a murine model of oral cancer. Clin Cancer Res 2003; 9 (8) 3183-3189
47 Lurje G, Lenz HJ. EGFR signaling and drug discovery. Oncology 2009; 77 (6) 400-410
48 Le Cras TD, Hardie WD, Fagan K, Whitsett JA, Korfhagen TR. Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-alpha. Am J Physiol Lung Cell Mol Physiol 2003; 285 (5) L1046-L1054
49 Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 2005; 112 (3) 423-431
50 Dahal BK, Cornitescu T, Tretyn A , et al. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med 2010; 181 (2) 158-167
51 Tuder RM, Yun JH. Vascular endothelial growth factor of the lung: friend or foe. Curr Opin Pharmacol 2008; 8 (3) 255-260
52 Kasahara Y, Tuder RM, Taraseviciene-Stewart L , et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000; 106 (11) 1311-1319
53 Partovian C, Adnot S, Eddahibi S , et al. Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertension. Am J Physiol 1998; 275 (6, Pt 2) H1948-H1956
54 Campbell AI, Zhao Y, Sandhu R, Stewart DJ. Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation 2001; 104 (18) 2242-2248
55 Taraseviciene-Stewart L, Kasahara Y, Alger L , et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 2001; 15 (2) 427-438
56 Taraseviciene-Stewart L, Scerbavicius R, Choe KH , et al. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2006; 291 (4) L668-L676
57 Grover TR, Parker TA, Zenge JP, Markham NE, Kinsella JP, Abman SH. Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 2003; 284 (3) L508-L517
58 Sata M, Saiura A, Kunisato A , et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002; 8 (4) 403-409
59 Gambaryan N, Perros F, Montani D, Cohen-Kaminsky S, Mazmanian GM, Humbert M. Imatinib inhibits bone marrow-derived c-kit+ cell mobilisation in hypoxic pulmonary hypertension. Eur Respir J 2010; 36 (5) 1209-1211
60 Gambaryan N, Perros F, Montani D , et al. Targeting of c-kit+ haematopoietic progenitor cells prevents hypoxic pulmonary hypertension. Eur Respir J 2011; 37 (6) 1392-1399
61 Perros F, Dorfmüller P, Souza R , et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J 2007; 29 (3) 462-468
62 Mitani Y, Ueda M, Maruyama K , et al. Mast cell chymase in pulmonary hypertension. Thorax 1999; 54 (1) 88-90
63 Heath D, Yacoub M. Lung mast cells in plexogenic pulmonary arteriopathy. J Clin Pathol 1991; 44 (12) 1003-1006
64 Dahal BK, Kosanovic D, Kaulen C , et al. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. Respir Res 2011; 12: 60
65 Metz M, Grimbaldeston MA, Nakae S, Piliponsky AM, Tsai M, Galli SJ. Mast cells in the promotion and limitation of chronic inflammation. Immunol Rev 2007; 217: 304-328
66 Okayama Y, Ra C, Saito H. Role of mast cells in airway remodeling. Curr Opin Immunol 2007; 19 (6) 687-693
67 Guignabert C, Montani D. Key roles of Src family tyrosine kinases in the integrity of the pulmonary vascular bed. Eur Respir J 2013; 41 (1) 3-4
68 Oda Y, Renaux B, Bjorge J, Saifeddine M, Fujita DJ, Hollenberg MD. cSrc is a major cytosolic tyrosine kinase in vascular tissue. Can J Physiol Pharmacol 1999; 77 (8) 606-617
69 Courboulin A, Paulin R, Giguère NJ , et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med 2011; 208 (3) 535-548
70 Nagaraj C, Tang B, Bálint Z , et al. Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries. Eur Respir J 2013; 41 (1) 85-95
71 Pullamsetti SS, Berghausen EM, Dabral S , et al. Role of Src tyrosine kinases in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol 2012; 32 (6) 1354-1365
72 Grünwald V, Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 2003; 95 (12) 851-867
73 O'Connell C, O'Callaghan DS, Gaine S. New drugs for pulmonary hypertension. European Respiratory Monograph 2012; 57: 233-246
74 Abe K, Toba M, Alzoubi A , et al. Tyrosine kinase inhibitors are potent acute pulmonary vasodilators in rats. Am J Respir Cell Mol Biol 2011; 45 (4) 804-808
75 Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411 (6835) 355-365
76 Schermuly RT, Dony E, Ghofrani HA , et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005; 115 (10) 2811-2821
77 Patterson KC, Weissmann A, Ahmadi T, Farber HW. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med 2006; 145 (2) 152-153
78 Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005; 353 (13) 1412-1413
79 Souza R, Sitbon O, Parent F, Simonneau G, Humbert M. Long term imatinib treatment in pulmonary arterial hypertension. Thorax 2006; 61 (8) 736
80 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 (9) 1171-1177
81 Humbert M. Impression, sunset. Circulation 2013; 127 (10) 1098-1100
82 Hoeper MM, Barst RJ, Bourge RC , et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 2013; 127 (10) 1128-1138
83 Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder DR. Imatinib-IPF Study Investigators. Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results. Am J Respir Crit Care Med 2010; 181 (6) 604-610
84 Henkens IR, Hazenoot T, Boonstra A , et al. Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension. Eur Respir J 2012;
85 Simonneau G, Hwang LJ, Teal S, Galie N. Incidence of subdural hematoma in patients with pulmonary arterial hypertension (PAH) in two randomized controlled clinical trials. Eur Respir J 2012; 40 (Suppl. 56): 941
86 Llovet JM, Ricci S, Mazzaferro V , et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (4) 378-390
87 Escudier B, Eisen T, Stadler WM , et al; TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356 (2) 125-134
88 Yu C, Bruzek LM, Meng XW , et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 2005; 24 (46) 6861-6869
89 Klein M, Schermuly RT, Ellinghaus P , et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 2008; 118 (20) 2081-2090
90 Moreno-Vinasco L, Gomberg-Maitland M, Maitland ML , et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics 2008; 33 (2) 278-291
91 Gomberg-Maitland M, Maitland ML, Barst RJ , et al. A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2010; 87 (3) 303-310
92 Maurer B, Reich N, Juengel A , et al. Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. Ann Rheum Dis 2012; 71 (8) 1382-1387
93 Efficacy, Safety, Tolerability and Pharmacokinetics (PK) of Nilotinib (AMN107) in Pulmonary Arterial Hypertension (PAH). Available at: http://www.clinicaltrials.gov . Identifier NCT01179737
94 Atallah E, Durand JB, Kantarjian H, Cortes J. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2007; 110 (4) 1233-1237
95 Cohen MH, Williams G, Johnson JR , et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 2002; 8 (5) 935-942
96 Kerkelä R, Grazette L, Yacobi R , et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12 (8) 908-916
97 Atallah E. Nilotinib cardiac toxicity: should we still be concerned?. Leuk Res 2011; 35 (5) 577-578
98 Atkins M, Jones CA, Kirkpatrick P. Sunitinib maleate. Nat Rev Drug Discov 2006; 5 (4) 279-280
99 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) 1329-1338
100 Chu TF, Rupnick MA, Kerkela R , et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007; 370 (9604) 2011-2019
101 Khakoo AY, Kassiotis CM, Tannir N , et al. Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer 2008; 112 (11) 2500-2508
102 Lombardo LJ, Lee FY, Chen P , et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004; 47 (27) 6658-6661
103 Kantarjian H, Shah NP, Hochhaus A , et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362 (24) 2260-2270
104 Kantarjian HM, Shah NP, Cortes JE , et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119 (5) 1123-1129
105 Orlandi EM, Rocca B, Pazzano AS, Ghio S. Reversible pulmonary arterial hypertension likely related to long-term, low-dose dasatinib treatment for chronic myeloid leukaemia. Leuk Res 2012; 36 (1) e4-e6
106 Dumitrescu D, Seck C, ten Freyhaus H, Gerhardt F, Erdmann E, Rosenkranz S. Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J 2011; 38 (1) 218-220
107 Mattei D, Feola M, Orzan F, Mordini N, Rapezzi D, Gallamini A. Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient. Bone Marrow Transplant 2009; 43 (12) 967-968
108 Rasheed W, Flaim B, Seymour JF. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res 2009; 33 (6) 861-864
109 Montani D, Bergot E, Günther S , et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012; 125 (17) 2128-2137
110 Mandegar M, Fung YC, Huang W, Remillard CV, Rubin LJ, Yuan JX. Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc Res 2004; 68 (2) 75-103
111 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
112 Zakrzewski D, Seferynska I, Warzocha K, Hryniewiecki T. Elevation of pulmonary artery pressure as a complication of nilotinib therapy for chronic myeloid leukemia. Int J Hematol 2012; 96 (1) 132-135
113 Keller-V Amsberg G, Brümmendorf TH. Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia. Expert Rev Anticancer Ther 2012; 12 (9) 1121-1127