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Dasatinib

Dasatinib is an orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations. SRC-family protein-tyrosine kinases interact with variety of cell-surface receptors and participate in intracellular signal transduction pathways; tumorigenic forms can occur through altered regulation or expression of the endogenous protein and by way of virally-encoded kinase genes. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

According to http://en.wikipedia.org/wiki/Dasatinib,  Dasatinib, also known as BMS-354825, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is also being assessed for use in metastatic melanoma. The drug is named after one of the inventor chemists, Jagabandhu Das, who was a member of the large discovery and development team at Bristol Myers Squibb. In a Phase I dose escalation study published in June 2006, dasatinib was tested in patients who were resistant to or who could not tolerate imatinib. Complete hematological responses were seen in 37 of 40 patients with chronic-phase CML. Major hematologic responses[4] were seen in 31 of 44 patients with accelerated-phase CML, CML in blast crisis, or Ph+ ALL.  Responses were maintained in 95% of patients with chronic-phase CML, with a median follow-up time of >12 months. In patients with accelerated-phase CML, 82% remained in remission, although with a median follow-up of only 5 months. Nearly all patients with CML in blast crisis or Ph+ ALL relapsed within 6 months.

DRUG DESCRIPTION

SPRYCEL (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2­chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4­pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.

Mechanism of Action

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ;. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.  In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

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195: Jabbour E, Soverini S. Understanding the role of mutations in therapeutic decision making for chronic myeloid leukemia. Semin Hematol. 2009 Apr;46(2 Suppl 3):S22-6. PubMed PMID: 19621546.

196: Fava C, Cortes J. Optimizing first-line therapy for patients with chronic myeloid leukemia. Semin Hematol. 2009 Apr;46(2 Suppl 3):S5-10. PubMed PMID: 19621543.

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207: Klamová H, Marková M, Moravcová J, Sisková M, Cetkovský P, Machová Poláková K. Response to treatment in women with chronic myeloid leukemia during pregnancy and after delivery. Leuk Res. 2009 Nov;33(11):1567-9. Epub 2009 Jul 5. PubMed PMID: 19580997.

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209: Sikkema AH, Diks SH, den Dunnen WF, ter Elst A, Scherpen FJ, Hoving EW, Ruijtenbeek R, Boender PJ, de Wijn R, Kamps WA, Peppelenbosch MP, de Bont ES. Kinome profiling in pediatric brain tumors as a new approach for target discovery. Cancer Res. 2009 Jul 15;69(14):5987-95. Epub 2009 Jun 30. PubMed PMID: 19567681.

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211: Suo G, Jiang Y, Cowan B, Wang JY. Platelet-derived growth factor C is upregulated in human uterine fibroids and regulates uterine smooth muscle cell growth. Biol Reprod. 2009 Oct;81(4):749-58. Epub 2009 Jun 24. PubMed PMID: 19553600; PubMed Central PMCID: PMC2754888.

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216: Mauro MJ. Response dynamics in chronic-phase chronic myeloid leukemia. Clin Lymphoma Myeloma. 2009 Jun;9(3):217-22. Review. PubMed PMID: 19525190.

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218: Pichot CS, Hartig SM, Xia L, Arvanitis C, Monisvais D, Lee FY, Frost JA, Corey SJ. Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Br J Cancer. 2009 Jul 7;101(1):38-47. Epub 2009 Jun 9. PubMed PMID: 19513066; PubMed Central PMCID: PMC2713704.

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221: Galinsky I, Buchanan S. Practical management of dasatinib for maximum patient benefit. Clin J Oncol Nurs. 2009 Jun;13(3):329-35. Review. PubMed PMID: 19502192.

222: Bryant G. A once-daily dasatinib dosing strategy for chronic myeloid leukemia. Clin J Oncol Nurs. 2009 Jun;13(3):316-23. PubMed PMID: 19502190.

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224: Chen Y, Agarwal S, Shaik NM, Chen C, Yang Z, Elmquist WF. P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib. J Pharmacol Exp Ther. 2009 Sep;330(3):956-63. Epub 2009 Jun 2. PubMed PMID: 19491323.

225: Apperley JF, Cortes JE, Kim DW, Roy L, Roboz GJ, Rosti G, Bullorsky EO, Abruzzese E, Hochhaus A, Heim D, de Souza CA, Larson RA, Lipton JH, Khoury HJ, Kim HJ, Sillaber C, Hughes TP, Erben P, Van Tornout J, Stone RM. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol. 2009 Jul 20;27(21):3472-9. Epub 2009 Jun 1. PubMed PMID: 19487385.

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227: Storey S. Chronic myelogenous leukaemia market. Nat Rev Drug Discov. 2009 Jun;8(6):447. PubMed PMID: 19483705.

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230: Mauro MJ. Appropriate sequencing of tyrosine kinase inhibitors in chronic myelogenous leukemia: when to change? A perspective in 2009. Curr Opin Hematol. 2009 Mar;16(2):135-9. Review. PubMed PMID: 19468276.

231: Tecchio C, Nichele I, Todeschini G, Pizzolo G, Ambrosetti A. Dasatinib-induced response in a rare case of chronic lymphocytic leukaemia associated with chronic myeloid leukaemia. Br J Haematol. 2009 Jul;146(2):222-3. Epub 2009 May 19. PubMed PMID: 19466973.

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234: Sos ML, Michel K, Zander T, Weiss J, Frommolt P, Peifer M, Li D, Ullrich R, Koker M, Fischer F, Shimamura T, Rauh D, Mermel C, Fischer S, Stückrath I, Heynck S, Beroukhim R, Lin W, Winckler W, Shah K, LaFramboise T, Moriarty WF, Hanna M, Tolosi L, Rahnenführer J, Verhaak R, Chiang D, Getz G, Hellmich M, Wolf J, Girard L, Peyton M, Weir BA, Chen TH, Greulich H, Barretina J, Shapiro GI, Garraway LA, Gazdar AF, Minna JD, Meyerson M, Wong KK, Thomas RK. Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. J Clin Invest. 2009 Jun;119(6):1727-40. doi: 10.1172/JCI37127. Epub 2009 May 18. PubMed PMID: 19451690; PubMed Central PMCID: PMC2689116.

235: Hingorani P, Zhang W, Gorlick R, Kolb EA. Inhibition of Src phosphorylation alters metastatic potential of osteosarcoma in vitro but not in vivo. Clin Cancer Res. 2009 May 15;15(10):3416-22. Epub 2009 May 15. PubMed PMID: 19447875.

236: Tatarov O, Mitchell TJ, Seywright M, Leung HY, Brunton VG, Edwards J. SRC family kinase activity is up-regulated in hormone-refractory prostate cancer. Clin Cancer Res. 2009 May 15;15(10):3540-9. Epub 2009 May 15. PubMed PMID: 19447874.

237: Frigeri F, Arcamone M, Luciano L, Di Francia R, Pane F, Pinto A. Systemic dasatinib fails to prevent development of central nervous system progression in a patient with BCR-ABL unmutated Philadelphia chromosome-positive leukemia. Blood. 2009 May 14;113(20):5028-9. PubMed PMID: 19443672.

238: de Groot J, Milano V. Improving the prognosis for patients with glioblastoma: the rationale for targeting Src. J Neurooncol. 2009 Nov;95(2):151-63. Epub 2009 May 13. Review. PubMed PMID: 19436954.

239: Homsi J, Cubitt CL, Zhang S, Munster PN, Yu H, Sullivan DM, Jove R, Messina JL, Daud AI. Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma. Melanoma Res. 2009 Jun;19(3):167-75. PubMed PMID: 19434004.

240: De Francia S, D'Avolio A, De Martino F, Pirro E, Baietto L, Siccardi M, Simiele M, Racca S, Saglio G, Di Carlo F, Di Perri G. New HPLC-MS method for the simultaneous quantification of the antileukemia drugs imatinib, dasatinib, and nilotinib in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jun 15;877(18-19):1721-6. Epub 2009 Apr 24. PubMed PMID: 19428316.

241: Visani G, Piccaluga P, Malagola M, Isidori A. Efficacy of dasatinib in conjunction with alpha-interferon for the treatment of imatinib-resistant and dasatinib-resistant Ph+ acute lymphoblastic leukemia. Leukemia. 2009 Sep;23(9):1687-8. Epub 2009 May 7. PubMed PMID: 19421228.

242: Quintás-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood. 2009 Jul 9;114(2):261-3. Epub 2009 May 4. PubMed PMID: 19414863.

243: Kurebayashi J. Possible treatment strategies for triple-negative breast cancer on the basis of molecular characteristics. Breast Cancer. 2009;16(4):275-80. Epub 2009 May 1. PubMed PMID: 19408071.

244: Taylor MJ, Scuffham PA. Pharmacoeconomic benefits of dasatinib in the treatment of imatinib-resistant patients with chronic myelogenous leukemia. Expert Rev Pharmacoecon Outcomes Res. 2009 Apr;9(2):117-21. Review. PubMed PMID: 19402798.

245: Quintás-Cardama A, Cortes JE, O'Brien S, Ravandi F, Borthakur G, Liu D, Bleickardt E, Chen TT, Kantarjian HM. Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia. Cancer. 2009 Jul 1;115(13):2912-21. PubMed PMID: 19402171.

246: Nautiyal J, Majumder P, Patel BB, Lee FY, Majumdar AP. Src inhibitor dasatinib inhibits growth of breast cancer cells by modulating EGFR signaling. Cancer Lett. 2009 Oct 8;283(2):143-51. Epub 2009 Apr 26. PubMed PMID: 19398150.

247: Ustun C, Jillella AP, Salama ME. Dasatinib induces complete cytogenetic response and loss of F359C in an imatinib resistant chronic myelocytic leukemia patient. Am J Hematol. 2009 Jun;84(6):386-7. PubMed PMID: 19391130.

248: Gruber F, Mustjoki S, Porkka K. Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome-positive acute lymphoblastic leukaemia. Br J Haematol. 2009 Jun;145(5):581-97. Epub 2009 Apr 15. Review. PubMed PMID: 19388927.

249: Faderl S, Pal A, Bornmann W, Albitar M, Maxwell D, Van Q, Peng Z, Harris D, Liu Z, Hazan-Halevy I, Kantarjian HM, Estrov Z. Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells. Cancer Res. 2009 May 1;69(9):3910-7. Epub 2009 Apr 21. PubMed PMID: 19383925.

250: Kopetz S, Lesslie DP, Dallas NA, Park SI, Johnson M, Parikh NU, Kim MP, Abbruzzese JL, Ellis LM, Chandra J, Gallick GE. Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res. 2009 May 1;69(9):3842-9. Epub 2009 Apr 21. PubMed PMID: 19383922; PubMed Central PMCID: PMC2709758.

251: Hantschel O, Gstoettenbauer A, Colinge J, Kaupe I, Bilban M, Burkard TR, Valent P, Superti-Furga G. The chemokine interleukin-8 and the surface activation protein CD69 are markers for Bcr-Abl activity in chronic myeloid leukemia. Mol Oncol. 2008 Oct;2(3):272-81. Epub 2008 Jul 23. PubMed PMID: 19383348.

252: Kelly K, Swords R, Mahalingam D, Padmanabhan S, Giles FJ. Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors. Target Oncol. 2009 Apr;4(2):99-105. Epub 2009 Apr 21. Review. PubMed PMID: 19381453.

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254: Pal SK, Gupta RK, Dosik G, Figlin RA. Concomitant renal cell carcinoma and chronic myelogenous leukemia: use of a targeted approach. Curr Oncol. 2009 Mar;16(2):44-7. PubMed PMID: 19370179; PubMed Central PMCID: PMC2669228.

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256: Cannella L, Breccia M, Stefanizzi C, Napoleone L, Santopietro M, Alimena G. Dasatinib overcomes imatinib and nilotinib failure in Philadelphia chromosome positive chronic myeloid leukemia with different mechanisms of resistance. Leuk Lymphoma. 2009 May;50(5):848-50. PubMed PMID: 19367499.

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280: Sakamaki H, Ishizawa K, Taniwaki M, Fujisawa S, Morishima Y, Tobinai K, Okada M, Ando K, Usui N, Miyawaki S, Utsunomiya A, Uoshima N, Nagai T, Naoe T, Motoji T, Jinnai I, Tanimoto M, Miyazaki Y, Ohnishi K, Iida S, Okamoto S, Seriu T, Ohno R. Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol. 2009 Apr;89(3):332-41. Epub 2009 Mar 5. PubMed PMID: 19263190.

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294: Tallman M. Existing and emerging therapeutic options for the treatment of acute myeloid leukemia. Clin Adv Hematol Oncol. 2008 Nov;6(11):3-5. PubMed PMID: 19205108.

295: Komarova NL, Katouli AA, Wodarz D. Combination of two but not three current targeted drugs can improve therapy of chronic myeloid leukemia. PLoS One. 2009;4(2):e4423. Epub 2009 Feb 10. PubMed PMID: 19204794; PubMed Central PMCID: PMC2635955.

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301: Saad F. Src as a therapeutic target in men with prostate cancer and bone metastases. BJU Int. 2009 Feb;103(4):434-40. Epub 2008 Dec 22. Review. PubMed PMID: 19154462.

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303: Rea D, Raffoux E, Cayuela JM, Maarek O, Dombret H. Sustained major molecular response in the absence of any antileukaemic therapy after dasatinib treatment and autologous peripheral blood stem cell transplantation in a patient with imatinib-resistant myeloblastic-phase chronic myeloid leukaemia. Leukemia. 2009 Jun;23(6):1158-9. Epub 2009 Jan 8. PubMed PMID: 19151779.

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307: Valent P, Lion T, Wolf D, Sillaber C, Agis H, Petzer A, Lang A, Kalhs P, Geissler D, Greil R, Linkesch W, Burgstaller S, Thaler J, Gastl G. Diagnostic algorithms, monitoring, prognostication, and therapy in chronic myeloid leukemia (CML): a proposal of the Austrian CML platform. Wien Klin Wochenschr. 2008;120(21-22):697-709. PubMed PMID: 19116712.

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309: 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 Jun;43(12):967-8. Epub 2008 Dec 22. PubMed PMID: 19104491.

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313: Yanada M, Ohno R, Naoe T. Recent advances in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol. 2009 Jan;89(1):3-13. Epub 2008 Dec 18. Review. PubMed PMID: 19093166.

314: Conchon MR, Bendit I, Ferreira P, Lima W, Kumeda C, Dias L, Chamone Dde A, Dorlhiac-Llacer PE. Emergence of abnormal clone with monsomy 7 in Philadelphia negative cells of CML patients treated with tyrosine kinase inhibitors. Int J Hematol. 2009 Jan;89(1):123-5. Epub 2008 Dec 18. PubMed PMID: 19093165.

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316: Cervantes F. [Chronic myeloid leukemia 2008]. Med Clin (Barc). 2008 Nov 15;131(17):658-9. Review. Spanish. PubMed PMID: 19087793.

317: Gora-Tybor J, Robak T. Targeted drugs in chronic myeloid leukemia. Curr Med Chem. 2008;15(29):3036-51. Review. PubMed PMID: 19075651.

318: Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, Gambacorti-Passerini C, Boschelli F. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009 Jan 20;27(3):469-71. Epub 2008 Dec 15. PubMed PMID: 19075254.

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320: Kim DH, Kamel-Reid S, Chang H, Sutherland R, Jung CW, Kim HJ, Lee JJ, Lipton JH. Natural killer or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia. Haematologica. 2009 Jan;94(1):135-9. Epub 2008 Dec 9. PubMed PMID: 19066329; PubMed Central PMCID: PMC2625403.

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326: Sanchez-Guijo FM, Lopez-Jimenez J, Gonzalez T, Santamaría C, González M, Del Cañizo MC. Multitargeted sequential therapy with MK-0457 and dasatinib followed by stem cell transplantation for T315I mutated chronic myeloid leukemia. Leuk Res. 2009 Jun;33(6):e20-2. Epub 2008 Nov 26. PubMed PMID: 19038446.

327: Aichberger KJ, Sperr WR, Gleixner KV, Kretschmer A, Valent P. Treatment responses to cladribine and dasatinib in rapidly progressing aggressive mastocytosis. Eur J Clin Invest. 2008 Nov;38(11):869-73. PubMed PMID: 19021706.

328: Verstovsek S. Preclinical and clinical experience with dasatinib in Philadelphia chromosome-negative leukemias and myeloid disorders. Leuk Res. 2009 May;33(5):617-23. Epub 2008 Nov 14. Review. PubMed PMID: 19013641.

329: Buettner R, Mesa T, Vultur A, Lee F, Jove R. Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells. Mol Cancer Res. 2008 Nov;6(11):1766-74. PubMed PMID: 19010823; PubMed Central PMCID: PMC2768340.

330: Alkhatib R, Hennebelle T, Joha S, Idziorek T, Preudhomme C, Quesnel B, Sahpaz S, Bailleul F. Activity of elaeochytrin A from Ferula elaeochytris on leukemia cell lines. Phytochemistry. 2008 Dec;69(17):2979-83. Epub 2008 Nov 5. PubMed PMID: 18992904.

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332: Ustun C, Corless CL, Savage N, Fiskus W, Manaloor E, Heinrich MC, Lewis G, Ramalingam P, Kepten I, Jillella A, Bhalla K. Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT D816V. Leuk Res. 2009 May;33(5):735-41. Epub 2008 Nov 4. PubMed PMID: 18986703.

333: Rasheed W, Flaim B, Seymour JF. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res. 2009 Jun;33(6):861-4. Epub 2008 Nov 4. PubMed PMID: 18986702.

334: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Sep;30(7):543-88. PubMed PMID: 18985183.

335: Williams NK, Lucet IS, Klinken SP, Ingley E, Rossjohn J. Crystal structures of the Lyn protein tyrosine kinase domain in its Apo- and inhibitor-bound state. J Biol Chem. 2009 Jan 2;284(1):284-91. Epub 2008 Nov 4. PubMed PMID: 18984583.

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338: Weiss GJ, Kingsley C. Pathway targets to explore in the treatment of non-small cell lung cancer. J Thorac Oncol. 2008 Nov;3(11):1342-52. PubMed PMID: 18978571.

339: Jarkowski A, Sweeney RP. Nilotinib: a new tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Pharmacotherapy. 2008 Nov;28(11):1374-82. Review. PubMed PMID: 18956997.

340: Day E, Waters B, Spiegel K, Alnadaf T, Manley PW, Buchdunger E, Walker C, Jarai G. Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. Eur J Pharmacol. 2008 Dec 3;599(1-3):44-53. Epub 2008 Oct 11. PubMed PMID: 18938156.

341: Penel N, Adenis A. Publication biases and phase II trials investigating anticancer targeted therapies. Invest New Drugs. 2009 Jun;27(3):287-8. Epub 2008 Oct 18. PubMed PMID: 18931825.

342: Bewry NN, Nair RR, Emmons MF, Boulware D, Pinilla-Ibarz J, Hazlehurst LA. Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol Cancer Ther. 2008 Oct;7(10):3169-75. PubMed PMID: 18852120; PubMed Central PMCID: PMC2676735.

343: Yano A, Tsutsumi S, Soga S, Lee MJ, Trepel J, Osada H, Neckers L. Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15541-6. PubMed PMID: 18840695; PubMed Central PMCID: PMC2563126.

344: Holstein SA, Stokes JB, Hohl RJ. Renal failure and recovery associated with second-generation Bcr-Abl kinase inhibitors in imatinib-resistant chronic myelogenous leukemia. Leuk Res. 2009 Feb;33(2):344-7. Epub 2008 Oct 2. PubMed PMID: 18835038.

345: Kubuki Y. [Management of chronic myeloid leukemia]. Rinsho Ketsueki. 2008 Oct;49(10):1401-10. Review. Japanese. PubMed PMID: 18833925.

346: Usui N. [Management of acute lymphoblastic leukemia]. Rinsho Ketsueki. 2008 Oct;49(10):1374-85. Review. Japanese. PubMed PMID: 18833922.

347: Okabe S, Tauchi T, Ohyashiki K. Characteristics of dasatinib- and imatinib-resistant chronic myelogenous leukemia cells. Clin Cancer Res. 2008 Oct 1;14(19):6181-6. PubMed PMID: 18829496.

348: Cony-Makhoul P, Bergeron A, Corm S, Dubruille V, Rea D, Rigal-Huguet F, Nicolini FE. [Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias]. Bull Cancer. 2008 Sep;95(9):805-11. French. PubMed PMID: 18829412.

349: Cang S, Liu D. P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia. J Hematol Oncol. 2008 Oct 1;1:15. Review. PubMed PMID: 18828913; PubMed Central PMCID: PMC2567340.

350: Zeidan A, Wang ES, Wetzler M. What is imatinib-resistant chronic myeloid leukemia? Identifying and managing loss of response. Clin Adv Hematol Oncol. 2008 Sep;6(9):673-83. PubMed PMID: 18827790.

351: Eustace AJ, Crown J, Clynes M, O'Donovan N. Preclinical evaluation of dasatinib, a potent Src kinase inhibitor, in melanoma cell lines. J Transl Med. 2008 Sep 29;6:53. PubMed PMID: 18823558; PubMed Central PMCID: PMC2569026.

352: Jabbour E, Kantarjian HM, Jones D, Reddy N, O'Brien S, Garcia-Manero G, Burger J, Cortes J. Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood. 2008 Dec 15;112(13):4839-42. Epub 2008 Sep 25. PubMed PMID: 18818391.

353: Chang Q, Jorgensen C, Pawson T, Hedley DW. Effects of dasatinib on EphA2 receptor tyrosine kinase activity and downstream signalling in pancreatic cancer. Br J Cancer. 2008 Oct 7;99(7):1074-82. Epub 2008 Sep 16. PubMed PMID: 18797457; PubMed Central PMCID: PMC2567084.

354: Hallaert DY, Jaspers A, van Noesel CJ, van Oers MH, Kater AP, Eldering E. c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches. Blood. 2008 Dec 15;112(13):5141-9. Epub 2008 Sep 16. PubMed PMID: 18796631.

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501: Verkhivker GM. Exploring sequence-structure relationships in the tyrosine kinome space: functional classification of the binding specificity mechanisms for cancer therapeutics. Bioinformatics. 2007 Aug 1;23(15):1919-26. Epub 2007 May 30. PubMed PMID: 17537753.

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