Tyrosine kinase inhibitors: Views of selectivity, sensitivity, and clinical performance

Annual Review of Pharmacology and Toxicology

Volumn 53, Issue , 2013, Pages 161-185

  Levitzki, Alexander ^a  

^a HEBREW UNIVERSITY OF JERUSALEM   (Israel)

Author keywords

cancer therapy; genomic instability; oncogene addiction; tyrphostins

Indexed keywords

6,7 DIMETHOXY 2 PHENYLQUINOXALINE; 6,7 DIMETHYL 2 PHENYLQUINOXALINE; ANTINEOPLASTIC AGENT; AXITINIB; BM 354825; CETUXIMAB; CRIZOTINIB; DASATINIB; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; ERLOTINIB; GEFITINIB; IMATINIB; INC 424; IPILIMUMAB; JANUS KINASE 2 INHIBITOR; LAPATINIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; N BENZYL 2 CYANO 3 (3,4 DIHYDROXYPHENYL)ACRYLAMIDE; NERATINIB; NILOTINIB; PANITUMUMAB; PAZOPANIB; PERTUZUMAB; PROTEIN TYROSINE KINASE INHIBITOR; RUXOLITINIB; SORAFENIB; SUNITINIB; TOFACITINIB; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANDETANIB; VEMURAFENIB;

ACUTE LYMPHOBLASTIC LEUKEMIA; ALLOSTERISM; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ASTHMA; BINDING AFFINITY; BREAST CANCER; CANCER CELL; CELL PROLIFERATION; CHRONIC EOSINOPHILIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; CHRONIC MYELOMONOCYTIC LEUKEMIA; CYTOTOXICITY; DRUG BINDING SITE; DRUG EFFICACY; DRUG HALF LIFE; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG TARGETING; ENZYME ACTIVITY; GASTROINTESTINAL STROMAL TUMOR; GENE AMPLIFICATION; GRAFT REJECTION; HUMAN; IMMUNOLOGICAL TOLERANCE; KIDNEY CARCINOMA; LEUKEMIA; LUNG FIBROSIS; LUNG NON SMALL CELL CANCER; MELANOMA; METASTASIS; MYELOFIBROSIS; MYELOPROLIFERATIVE DISORDER; NONHUMAN; ONCOGENE; OVERALL SURVIVAL; PANCREAS CANCER; PAPILLOMA; POLYCYTHEMIA VERA; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEIN DOMAIN; PROTEIN PHOSPHORYLATION; PULMONARY HYPERTENSION; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; THYROID MEDULLARY CARCINOMA; TREATMENT RESPONSE;

ANIMALS; BENZAMIDES; HUMANS; NEOPLASMS; PIPERAZINES; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; PYRIMIDINES;

EID: 84872243145     PISSN: 03621642     EISSN: 15454304     Source Type: Book Series    
DOI: 10.1146/annurev-pharmtox-011112-140341     Document Type: Review

References (106)

1. Hanks SK, Quinn AM, Hunter T. 1988. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:42-52
2. Hanks SK, Hunter T. 1995. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9:576-96
3. Yaish P, Gazit A, Gilon C, Levitzki A. 1988. Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science 242:933-35
4. Gazit A, Yaish P, Gilon C, Levitzki A. 1989. Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors. J. Med. Chem. 32:2344-52
5. Kovalenko M, Gazit A, Bohmer A, Rorsman C, Ronnstrand L, et al. 1994. Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. Cancer Res. 54:6106-14
6. Gazit A, AppH,McMahon G, Chen J, Levitzki A, Bohmer FD. 1996. Tyrphostins. 5. Potent inhibitors of platelet-derived growth factor receptor tyrosine kinase: structure-activity relationships in quinoxalines, quinolines, and indole tyrphostins. J. Med. Chem. 39:2170-77
7. Osherov N, Levitzki A. 1994. Epidermal-growth-factor-dependent activation of the Src-family kinases. Eur. J. Biochem. 225:1047-53
8. Ward WH, Cook PN, Slater AM,Davies DH, Holdgate GA, Green LR. 1994. Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem. Pharmacol. 48:659-66
9. Kovalenko M, Ronnstrand L, Heldin CH, Loubtchenkov M, Gazit A, et al. 1997. Phosphorylation sitespecific inhibition of platelet-derived growth factor β-receptor autophosphorylation by the receptor blocking tyrphostin AG1296. Biochemistry 36:6260-69
10. Lipson KE, Pang L,Huber LJ, Chen H, Tsai JM, et al. 1998. Inhibition of platelet-derived growth factor and epidermal growth factor receptor signaling events after treatment of cells with specific synthetic inhibitors of tyrosine kinase phosphorylation. J. Pharmacol. Exp. Ther. 285:844-52
11. Gazit A, Osherov N, Posner I, Bar-Sinai A, Gilon C, Levitzki A. 1993. Tyrphostins. III. Structureactivity relationship studies of α-substituted benzylidenemalononitrile 5-S-aryltyrphostins. J. Med. Chem. 36:3556-64
12. Gazit A, Osherov N, Posner I, Yaish P, Poradosu E, et al. 1991. Tyrphostins. II. Heterocyclic and α-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. J. Med. Chem. 34:1896-907
13. Osherov N, Gazit A, Gilon C, Levitzki A. 1993. Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins. J. Biol. Chem. 268:11134-42
14. Levitzki A, Mishani E. 2006. Tyrphostins and other tyrosine kinase inhibitors. Annu. Rev. Biochem. 75:93-109
15. Hunter T. 2007. Treatment for chronic myelogenous leukemia: the long road to imatinib. J. Clin. Investig. 117:2036-43
16. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, et al. 2012. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 366:707-14
17. Levitzki A. 1999. Protein tyrosine kinase inhibitors as novel therapeutic agents. Pharmacol. Ther. 82:231-39
18. Blum G, Gazit A, Levitzki A. 2003. Development of new insulin-like growth factor-1 receptor kinase inhibitors using catechol mimics. J. Biol. Chem. 278:40442-54
19. Blum G, Gazit A, Levitzki A. 2000. Substrate competitive inhibitors of IGF-1 receptor kinase. Biochemistry 39:15705-12
20. Steiner L, Blum G, Friedmann Y, Levitzki A. 2007. ATP non-competitive IGF-1 receptor kinase inhibitors as lead anti-neoplastic and anti-papilloma agents. Eur. J. Pharmacol. 562:1-11
21. Posner I, Engel M, Gazit A, Levitzki A. 1994. Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program. Mol. Pharmacol. 45:673-83
22. Banai S, Wolf Y, Golomb G, Pearle A, Waltenberger J, et al. 1998. PDGF-receptor tyrosine kinase blocker AG1295 selectively attenuates smooth muscle cell growth in vitro and reduces neointimal formation after balloon angioplasty in swine. Circulation 97:1960-69
23. Gazit A, Yee K, Uecker A, Bohmer FD, Sjoblom T, et al. 2003. Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit. Bioorg. Med. Chem. 11:2007-18
24. Banai S, Gertz SD, Gavish L, Chorny M, Perez LS, et al. 2004. Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries. Cardiovasc. Res. 64:165-71
25. Hassan AQ, Sharma SV, Warmuth M. 2010. Allosteric inhibition of BCR-ABL. Cell Cycle 9:3710-14
26. Reuveni H, Flashner E, Steiner L, Makedonski K, Song R, et al. 2012. Targeting insulin receptor substrates for destruction as a therapeutic modality for cancers. Presented at Annu. Meet. Israeli Soc. Cancer Res., 4th, Ramat-Gan 26a. Reuveni H, Levitzki A, Steiner L, Sasson R, Ben-David I, Wiessberg A. 2008. Novel protein kinase modulators and therapeutic uses thereof. PCT Patent WO/2008/068751.PCT/IL2007/001494. http://patent.ipexl.com/WO/ 2008ZZSLASHZZ068751.html
27. Parrizas M, Gazit A, Levitzki A, Wertheimer E, LeRoith D. 1997. Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins. Endocrinology 138:1427-33
28. Hall J, Aulabaugh A, Rajamohan F, Liu S, Kaila N, et al. 2012. Biophysical and mechanistic insights into a novel allosteric inhibitor of spleen tyrosine kinase. J. Biol. Chem. 287:7717-27
29. Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. 2012. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin. Ther. Targets 16:15-31
30. Vecchione L, Jacobs B, Normanno N, Ciardiello F, Tejpar S. 2011. EGFR-targeted therapy. Exp. Cell Res. 317:2765-71
31. Lyall RM, Zilberstein A, Gazit A, Gilon C, Levitzki A, Schlessinger J. 1989. Tyrphostins inhibit epidermal growth factor (EGF)-receptor tyrosine kinase activity in living cells and EGF-stimulated cell proliferation. J. Biol. Chem. 264:14503-9
32. Carter CA, Giaccone G. 2012. Treatment of nonsmall cell lung cancer: overcoming the resistance to epidermal growth factor receptor inhibitors. Curr. Opin. Oncol. 24:123-29
33. Bria E, Milella M, Cuppone F,Novello S, Ceribelli A, et al. 2011. Outcome of advancedNSCLC patients harboring sensitizing EGFRmutations randomized to EGFRtyrosine kinase inhibitors or chemotherapy as first-line treatment: a meta-analysis. Ann. Oncol. 22:2277-85
34. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, et al. 2010. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362:2380-88
35. Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, et al. 2010. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J. Clin. Oncol. 28:1301-7
36. Tefferi A. 2012. JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths. Blood 119(12):2721-30
37. Seavey MM, Dobrzanski P. 2012. The many faces of Janus kinase. Biochem. Pharmacol. 83:1136-45
38. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, et al. 2012. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N. Engl. J. Med. 366:787-98
39. Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, et al. 1996. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379:645-48
40. Weinstein IB. 2002. Cancer: Addiction to oncogenes-the Achilles heal of cancer. Science 297:63-64
41. Settleman J. 2012. Oncogene addiction. Curr. Biol. 22:R43-44
42. Benhar M, Engelberg D, Levitzki A. 2002. ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep. 3:420-25
43. Benhar M, Dalyot I, Engelberg D, Levitzki A. 2001. Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol. Cell. Biol. 21:6913-26
44. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, et al. 2012. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin. Cancer Res. 18(5):1472-82
45. Suda K, Tomizawa K, Osada H, Maehara Y, Yatabe Y, et al. 2011. Conversion from the "oncogene addiction" to "drug addiction" by intensive inhibition of the EGFR and MET in lung cancer with activating EGFR mutation. Lung Cancer 76(3):292-99
46. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, et al. 2010. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141:69-80
47. Levitzki A, Klein S. 2010. Signal transduction therapy of cancer. Mol. Aspects Med. 31:287-329
48. Lee SM. 2006. Is EGFR expression important in non-small cell lung cancer? Thorax 61:98-99
49. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, et al. 2011. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J. Clin. Oncol. 29:2866-74
50. Krumbach R, Schuler J,Hofmann M, Giesemann T, Fiebig HH, Beckers T. 2011. Primary resistance to cetuximab in a panel of patient-derived tumour xenograft models: activation ofMET as one mechanism for drug resistance. Eur. J. Cancer 47:1231-43
51. Wan X,Harkavy B, Shen N, Grohar P,Helman LJ. 2007. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26:1932-40
52. Levitzki A. 1992. Tyrphostins: tyrosine kinase blockers as novel antiproliferative agents and dissectors of signal transduction. FASEB J. 6:3275-82
53. Levitzki A. 1994. Signal-transduction therapy. A novel approach to diseasemanagement. Eur. J. Biochem. 226:1-13
54. Deshpande H, Marler V, Sosa JA. 2011. Clinical utility of vandetanib in the treatment of patients with advanced medullary thyroid cancer. OncoTargets Ther. 4:209-15
55. Koch L. 2012. Pharmacotherapy: vandetanib-a new therapeutic option in advanced medullary thyroid cancer. Nat. Rev. Endocrinol. 8:1
56. Doebele RC, Conkling P, Traynor AM, Otterson GA, Zhao Y, et al. 2012. A phase I, open-label doseescalation study of continuous treatment with BIBF 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer. Ann. Oncol. 23(8):2094-102
57. Ramalingam SS, Spigel DR,Chen D, Steins MB, Engelman JA, et al. 2011. Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer. J. Clin. Oncol. 29:4574-80
58. Klein S, Levitzki A. 2009. Targeting the EGFR and the PKB pathway in cancer. Curr. Opin. Cell Biol. 21:185-93
59. Wang J, Gui Z, Deng L, Sun M, Guo R, et al. 2012. c-Met upregulates aquaporin 3 expression in human gastric carcinoma cells via the ERK signalling pathway. Cancer Lett. 319:109-17
60. Wang W, Li Q, Takeuchi S, Yamada T, Koizumi H, et al. 2012. Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer. Clin. Cancer Res. 18:1663-71
61. Kosaka T, Yamaki E, Mogi A, Kuwano H. 2011. Mechanisms of resistance to EGFR TKIs and development of a new generation of drugs in non-small-cell lung cancer. J. Biomed. Biotechnol. 2011:165214
62. Nitta M, Kozono D, Kennedy R, Stommel J, Ng K, et al. 2010. Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy. PLoS ONE 5:e10767
63. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, et al. 2012. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485:55-61
64. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, et al. 2010. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargetingMEK and IGF-1R/PI3K. Cancer Cell 18:683-95
65. Ahn ER, Vogel CL. 2012. Dual HER2-targeted approaches in HER2-positive breast cancer. Breast Cancer Res. Treat. 131:371-83
66. Arribas J, Baselga J, Pedersen K, Parra-Palau JL. 2011. p95HER2 and breast cancer. Cancer Res. 71:1515-19
67. Schutz FA, Choueiri TK, Sternberg CN. 2011. Pazopanib: clinical development of a potent antiangiogenic drug. Crit. Rev. Oncol. Hematol. 77:163-71
68. Ńegrier S, Raymond E. 2012. Antiangiogenic treatments and mechanisms of action in renal cell carcinoma. Investig. New Drugs 30(4):1791-801
69. Takahashi S. 2011. Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol. Pharm. Bull. 34:1785-88
70. Saigal B, Glisson BS, Johnson FM. 2008. Dose-dependent and sequence-dependent cytotoxicity of erlotinib and docetaxel in head and neck squamous cell carcinoma. Anticancer Drugs 19:465-75
71. Piperdi B, Ling YH, Perez-Soler R. 2007. Schedule-dependent interaction between the proteosome inhibitor bortezomib and the EGFR-TK inhibitor erlotinib in human non-small cell lung cancer cell lines. J. Thorac. Oncol. 2:715-21
72. Andersson U, Johansson D, Behnam-Motlagh P, Johansson M, Malmer B. 2007. Treatment schedule is of importance when gefitinib is combined with irradiation of glioma and endothelial cells in vitro. Acta Oncol. 46:951-60
73. Gilbert J, Rudek MA, Higgins MJ, Zhao M, Bienvenu S, et al. 2012. A phase I trial of erlotinib and concurrent chemoradiotherapy for stage III and IV (M0) squamous cell carcinoma of the head and neck. Clin. Cancer Res. 18:1735-42
74. Burchert A,M̈ uller MC, Kostrewa P, Erben P, Bostel T, et al. 2010. Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. J. Clin. Oncol. 28:1429-35
75. Hardan I, Stanevsky A, Volchek Y, Tohami T, Amariglio N, et al. 2012. Treatment with interferon alpha prior to discontinuation of imatinib in patients with chronic myeloid leukemia. Cytokine 57:290-93
76. Legros L, Ebran N, Stebe E, Rousselot P, Rea D, et al. 2012. Imatinib sensitizesT-cell lymphocytes from chronic myeloid leukemia patients to FasL-induced cell death: a brief communication. J. Immunother. 35:154-58
77. Appel S, Boehmler AM, Grunebach F, Muller MR, Rupf A, et al. 2004. Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood 103:538-44
78. Cwynarski K, Laylor R, Macchiarulo E, Goldman J, Lombardi G, et al. 2004. Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. Leukemia 18:1332-39
79. Dietz AB, Souan L,Knutson GJ, Bulur PA, Litzow MR,Vuk-Pavlovic S. 2004. Imatinibmesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood 104:1094-99
80. Daniels JM, Vonk-Noordegraaf A, Janssen JJ, Postmus PE, van Altena R. 2009. Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia. Eur. Respir. J. 33:670-72
81. van Dongen M, Savage ND, Jordanova ES, Briaire-de Bruijn IH, Walburg KV, et al. 2010. Antiinflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor-treated gastrointestinal stromal tumors. Int. J. Cancer 127:899-909
82. Comin-Anduix B,Chodon T, SazegarH,Matsunaga D, Mock S, et al. 2010. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. Clin. Cancer Res. 16:6040-48
83. Karck M, Meliss R, Hestermann M, Mengel M, Pethig K, et al. 2002. Inhibition of aortic allograft vasculopathy by local delivery of platelet-derived growth factor receptor tyrosine-kinase blocker AG-1295. Transplantation 74:1335-41
84. Masuda S, Nakano K, Funakoshi K, Zhao G, Meng W, et al. 2011. Imatinib mesylate-incorporated nanoparticle-eluting stent attenuates in-stent neointimal formation in porcine coronary arteries. J. Atheroscler. Thromb. 18:1043-53
85. Ben-Bassat H. 2001. Biological activity of tyrosine kinase inhibitors: novel agents for psoriasis therapy. Curr. Opin. Investig. Drugs 2:1539-45
86. Powell TJ, Ben-Bassat H, Klein BY, Chen H, Shenoy N, et al. 1999. Growth inhibition of psoriatic keratinocytes by quinazoline tyrosine kinase inhibitors. Br. J. Dermatol. 141:802-10
87. West K. 2009. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr. Opin. Investig. Drugs 10:491-504
88. Boy MG, Wang C, Wilkinson BE, Chow VF, Clucas AT, et al. 2009. Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J. Investig. Dermatol. 129:2299-302
89. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, et al. 1999. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J. Pathol. 189:12-19
90. Ben-Bassat H, Rosenbaum-Mitrani S, Hartzstark Z, Shlomai Z, Kleinberger-Doron N, et al. 1997. Inhibitors of epidermal growth factor receptor kinase and of cyclin-dependent kinase 2 activation induce growth arrest, differentiation, and apoptosis of human papilloma virus 16-immortalized human keratinocytes. Cancer Res. 57:3741-50
91. Ben-Bassat H, Rosenbaum-Mitrani S, Hartzstark Z, Levitzki R, Chaouat M, et al. 1999. Tyrphostins that suppress the growth of human papilloma virus 16-immortalized human keratinocytes. J. Pharmacol. Exp. Ther. 290:1442-57
92. FleischmannR,CutoloM,Genovese MC, Lee EB, Kanik KS, et al. 2012. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 64:617-29
93. Levitzki A, Gazit A. 1995. Tyrosine kinase inhibition: an approach to drug development. Science 267:1782-88
94. Overbeek MJ, Boonstra A, Voskuyl AE, Vonk MC, Vonk-Noordegraaf A, et al. 2011. Platelet-derived growth factor receptor-β and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study. Arthritis Res. Ther. 13:R61
95. Daniels CE, Wilkes MC, Edens M, Kottom TJ, Murphy SJ, et al. 2004. Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis. J. Clin. Investig. 114:1308-16
96. Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder DR. 2010. Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results.Am. J. Respir. Crit.CareMed. 181:604-10
97. Chaudhary NI, Roth GJ, Hilberg F, Muller-Quernheim J, Prasse A, et al. 2007. Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur. Respir. J. 29:976-85
98. Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, et al. 2011. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N. Engl. J. Med. 365:1079-87
99. Kallio E, Koskinen P, Buchdunger E, Lemstrom K. 1999. Inhibition of obliterative bronchiolitis by platelet-derived growth factor receptor protein-tyrosine kinase inhibitor. Transplant. Proc. 31:187
100. Kallio EA, Koskinen PK, Aavik E, Buchdunger E, Lemstrom KB. 1999. Role of platelet-derived growth factor in obliterative bronchiolitis (chronic rejection) in the rat.Am. J. Respir. Crit. CareMed. 160:1324-32
101. Gosens R, Roscioni SS, Dekkers BG, Pera T, Schmidt M, et al. 2008. Pharmacology of airway smooth muscle proliferation. Eur. J. Pharmacol. 585:385-97
102. Zhu Y, Bertics PJ. 2011. Chemoattractant-induced signaling via the Ras-ERK and PI3K-Akt networks, along with leukotriene C4 release, is dependent on the tyrosine kinase Lyn in IL-5-and IL-3-primed human blood eosinophils. J. Immunol. 186:516-26
103. Duan Y, Learoyd J, Meliton AY, Clay BS, Leff AR, Zhu X. 2010. Inhibition of Pyk2 blocks airway inflammation and hyperresponsiveness in a mousemodel of asthma.Am. J. Respir. Cell Mol. Biol. 42:491-97
104. Makinde TO, Agrawal DK. 2011. Increased expression of angiopoietins and Tie2 in the lungs of chronic asthmatic mice. Am. J. Respir. Cell Mol. Biol. 44:384-93
105. Duan W, Kuo IC, Selvarajan S, Chua KY, Bay BH, Wong WS. 2003. Antiinflammatory effects of genistein, a tyrosine kinase inhibitor, on a guinea pig model of asthma. Am. J. Respir. Crit. Care Med. 167:185-92
106. Wong WS, Leong KP. 2004. Tyrosine kinase inhibitors: a new approach for asthma. Biochim. Biophys. Acta 1697:53-69