Cancer Treatment Reviews
Volume 36, Issue 6 , Pages 492-500 , October 2010

Dasatinib: A potent SRC inhibitor in clinical development for the treatment of solid tumors

  • John Araujo

      Affiliations

    • Corresponding Author InformationCorresponding author. Address: Genitourinary Center, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA. Tel.: +1 713 792 2830; fax: +1 713 792 1654.
  • ,
  • Christopher Logothetis

      Affiliations

    • Tel.: +1 713 563 7210; fax: +1 713 792 1654.

Received 22 December 2009 ,Revised 2 February 2010 ,Accepted 6 February 2010.

References 

  1. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105:2640–2653
  2. Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem. 2004;37:618–635
  3. Demetri GD. Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571). Eur J Cancer. 2002;38:S52–S59
  4. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183–232
  5. Gridelli C, Ardizzoni A, Ciardiello F, et al. Second-line treatment of advanced non-small cell lung cancer. J Thorac Oncol. 2008;3:430–440
  6. Ryan Q, Ibrahim A, Cohen MH, et al. FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist. 2008;13:1114–1119
  7. Goodman VL, Rock EP, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367–1373
  8. Kane RC, Farrell AT, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12:7271–7278
  9. Belsches-Jablonski AP, Biscardi JS, Peavy DR, Tice DA, Romney DA, Parsons SJ. Src family kinases and HER2 interactions in human breast cancer cell growth and survival. Oncogene. 2001;20:1465–1475
  10. Chou MT, Wang J, Fujita DJ. Src kinase becomes preferentially associated with the VEGFR, KDR/Flk-1, following VEGF stimulation of vascular endothelial cells. BMC Biochem. 2002;3:32
  11. DeMali KA, Godwin SL, Soltoff SP, Kazlauskas A. Multiple roles for Src in a PDGF-stimulated cell. Exp Cell Res. 1999;253:271–279
  12. 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;283:143–151
  13. Araujo J, Logothetis C. Targeting Src signaling in metastatic bone disease. Int J Cancer. 2008;124:1–6
  14. Boyce BF, Yoneda T, Lowe C, Soriano P, Mundy GR. Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J Clin Invest. 1992;90:1622–1627
  15. Myoui A, Nishimura R, Williams PJ, et al. C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res. 2003;63:5028–5033
  16. Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991;64:693–702
  17. Zhang XH, Wang Q, Gerald W, et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009;16:67–78
  18. 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;23:590–594
  19. 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;99:1074–1082
  20. 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;47:6658–6661
  21. Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res. 2008;14:352–359
  22. Fizazi K. The role of Src in prostate cancer. Ann Oncol. 2007;18:1765–1773
  23. Posadas EM, Al-Ahmadie H, Robinson VL, et al. FYN is overexpressed in human prostate cancer. BJU Int. 2009;103:171–177
  24. Lee LF, Louie MC, Desai SJ, et al. Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK. Oncogene. 2004;23:2197–2205
  25. Mendiratta P, Mostaghel E, Guinney J, et al. Genomic strategy for targeting therapy in castration-resistant prostate cancer. J Clin Oncol. 2009;27:2022–2029
  26. 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;15:3540–3549
  27. Nam S, Kim D, Cheng JQ, et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res. 2005;65:9185–9189
  28. Park SI, Zhang J, Phillips KA, et al. Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res. 2008;68:3323–3333
  29. Reissig D, Clement J, Sanger J, Berndt A, Kosmehl H, Bohmer FD. Elevated activity and expression of Src-family kinases in human breast carcinoma tissue versus matched non-tumor tissue. J Cancer Res Clin Oncol. 2001;127:226–230
  30. Finn RS, Dering J, Ginther C, et al. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res Treat. 2007;105:319–326
  31. Huang F, Reeves K, Han X, et al. Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. Cancer Res. 2007;67:2226–2238
  32. Dizdar O, Dede DS, Bulut N, Altundag K. Dasatinib may also inhibit c-Kit in triple negative breast cancer cell lines. Breast Cancer Res Treat. 2008;107:303
  33. Ferrer-Soler L, Vazquez-Martin A, Brunet J, Menendez JA, De LR, Colomer R. An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: Gefitinib (Iressa) -induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review). Int J Mol Med. 2007;20:3–10
  34. Viale G, Rotmensz N, Maisonneuve P, et al. Invasive ductal carcinoma of the breast with the “triple-negative” phenotype: prognostic implications of EGFR immunoreactivity. Breast Cancer Res Treat. 2009;116:317–328
  35. Biscardi JS, Belsches AP, Parsons SJ. Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. Mol Carcinog. 1998;21:261–272
  36. Weissenberger J, Steinbach JP, Malin G, Spada S, Rulicke T, Aguzzi A. Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene. 1997;14:2005–2013
  37. de Groot J, Milano V. Improving the prognosis for patients with glioblastoma: the rationale for targeting Src. J Neurooncol. 2009;95:151–163
  38. Du J, Bernasconi P, Clauser KR, et al. Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy. Nat Biotechnol. 2009;27:77–83
  39. Masaki T, Igarashi K, Tokuda M, et al. Pp60c-src activation in lung adenocarcinoma. Eur J Cancer. 2003;39:1447–1455
  40. Mazurenko NN, Kogan EA, Zborovskaya IB, Kisseljov FL. Expression of pp60c-src in human small cell and non-small cell lung carcinomas. Eur J Cancer. 1992;28:372–377
  41. Talamonti MS, Roh MS, Curley SA, Gallick GE. Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer. J Clin Invest. 1993;91:53–60
  42. Coppola D. Molecular prognostic markers in pancreatic cancer. Cancer Control. 2000;7:421–427
  43. Mandal M, Myers JN, Lippman SM, et al. Epithelial to mesenchymal transition in head and neck squamous carcinoma: association of Src activation with E-cadherin down-regulation, vimentin expression, and aggressive tumor features. Cancer. 2008;112:2088–2100
  44. Matsumoto T, Kiguchi K, Jiang J, et al. Development of transgenic mice that inducibly express an active form of c-Src in the epidermis. Mol Carcinog. 2004;40:189–200
  45. Johnson FM, Saigal B, Talpaz M, Donato NJ. Dasatinib (BMS-3548285) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carinoma and non-small cell lung cancer cell. Clin Cancer Res. 2005;11:6924–6932
  46. Song L, Morris M, Bagui T, Lee FY, Jove R, Haura EB. Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res. 2006;66:5542–5548
  47. Serrels A, Macpherson IR, Evans TR, et al. Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib. Mol Cancer Ther. 2006;5:3014–3022
  48. Trevino JG, Summy JM, Lesslie DP, et al. Inhibition of Src expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol. 2006;168:962–972
  49. 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;6:1766–1774
  50. 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;6:53
  51. Shor AC, Keschman EA, Lee FY, et al. Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival. Cancer Res. 2007;67:2800–2808
  52. Timeus F, Crescenzio N, Fandi A, Doria A, Foglia L, Cordero Di ML. In vitro antiproliferative and antimigratory activity of dasatinib in neuroblastoma and Ewing sarcoma cell lines. Oncol Rep. 2008;19:353–359
  53. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655–1664
  54. Yu EY, Wilding G, Posadas E, et al. Dasatinib in patients with hormone-refractory progressive prostate cancer: a phase II study. J Clin Oncol. 2008;26:288s;(abstract 5156)
  55. Luo FR, Camuso A, McGlinchey K, et al. Evaluation of anti-osteoclastic activity of the novel, oral multi-targeted kinase inhibitor dasatinib (BMS-354825). In: Proceedings of the molecular targets and cancer therapeutics meeting; 2005. p. 173 (abstract B178).
  56. Vandyke K, Dewar AL, Farrugia AN, et al. Therapeutic concentrations of dasatinib inhibit in vitro osteoclastogenesis. Leukemia. 2009;23:994–997
  57. Koreckij T, Nguyen H, Brown LG, Yu EY, Vessella RL, Corey E. Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br J Cancer. 2009;101:263–268
  58. Kopetz S, Shah AN, Gallick GE. Src continues aging: current and future clinical directions. Clin Cancer Res. 2007;13:7232–7236
  59. Wheeler DL, Lida M, Kruser TJ, et al. Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab. Cancer Biol Ther. 2009;8:696–703
  60. Pichot CS, Hartig SM, Xia L, et al. Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Br J Cancer. 2009;101:38–47
  61. Ueda Y, Igishi T, Hashimoto K, et al. Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: implication of c-Src and its inhibitor. Int J Oncol. 2009;34:689–696
  62. Homsi J, Cubitt CL, Zhang S, et al. Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma. Melanoma Res. 2009;19:167–175
  63. Kopetz S, Lesslie DP, Dallas NA, et al. Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res. 2009;69:3842–3849
  64. Johnson FM, Saigal B, Tran H, Donato NJ. Abrogation of signal transducer and activator of transcription 3 reactivation after Src kinase inhibition results in synergistic antitumor effects. Clin Cancer Res. 2007;13:4233–4244
  65. Milano V, Piao Y, LaFortune T, de Groot J. Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Mol Cancer Ther. 2009;8:394–406
  66. Yano A, Tsutsumi S, Soga S, et al. Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone. Proc Natl Acad Sci USA. 2008;105:15541–15546
  67. Bristol-Myers Squibb. Synopsis: final clinical study report for CA180021. Available at <http://ctr.bms.com/pdf//CA180021.pdf> (accessed March 2009).
  68. Demetri GD, Lo Russo P, Macpherson IR, et al. Phase I dose-escalation and pharmacokinetic study of dasatinib (BMS-354825), a Src and multi-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2009;15:6232–6240
  69. Vemulapalli S, Kurzrock R, Fritsche H, et al. Phase I open-labeled trial of gemcitabine and dasatinib in advanced solid tumors. J Clin Oncol. 2008;26:637s;(abstract 14626)
  70. Uronis HE, Bullock K, Blobe G, et al. A phase I study of gemcitabine plus dasatinib (GD) or gemcitabine plus dasatinib plus cetuximab (GDC) in refractory solid tumors. J Clin Oncol. 2009;27:(abstract e15506)
  71. Feinstein TM, Agrawal S, Stoller RG, Egorin M, Argiris A. Phase I and pharmacokinetic (PK) study of dasatinib (D) and cetuximab (C) in patients (pts) with advanced solid malignancies. J Clin Oncol. 2009;27:156s;(abstract 3540)
  72. Yu EY, Massard C, Gross M, et al. A phase II study of once-daily dasatinib for patients with castration-resistant prostate cancer (CA180085). J Clin Oncol. 2009;27:270s;(abstract 5147)
  73. Araujo J, Gallick G, Trudel G, et al. Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: a phase 1/2 study (CA180-086). In: Proc ASCO-GU; 2009 (abstract 177).
  74. Araujo J, Armstrong AJ, Braud EL, et al. Dasatinib and docetaxel combination treatment for patients with castration-resistant progressive prostate cancer: A phase I/II study (CA180086). J Clin Oncol. 2009;27:249s;(abstract 5061)
  75. Somlo G, Atzori F, Strauss L, et al. Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): phase I study CA180004. J Clin Oncol. 2009;27:43s;(abstract 1012)
  76. Finn RS, Bengala C, Ibrahim N, et al. Phase II trial of dasatinib in triple-negative breast cancer: results of study CA180059. Proc SABCS. 2008;(abstract 3118)
  77. Mayer E, Baurain J, Sparano J, et al. Dasatinib in advanced HER2/neu amplified and ER/PR-positive breast cancer: phase II study CA180088. J Clin Oncol. 2009;27:43s;(abstract 1011)
  78. Chiappori A, Tanvetyanon T, Williams CA, et al. Phase I trial evaluating the epidermal growth factor receptor inhibitor erlotinib in combination with the SRC kinase inhibitor dasatinib for patients with recurrent non-small cell lung cancer (NSCLC). J Clin Oncol. 2008;26:635s;(abstract 14605)
  79. Johnson FM, Tang X, Tran H, et al. Phase II study of dasatinib in non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27:(abstract e19015)
  80. Reardon D, Desjardins A, Vredenburgh J, et al. A Phase I trial of dasatinib (SPRYCEL) and erlotinib (TARCEVA) for patients with recurrent malignant glioma. Neuro-Oncology. 2008;10:(abstract MA-85)
  81. Lassman AB, Wang M, Gilbert MW, et al. Phase 2 trial of dasatinib in patients with recurrent glioblastoma (RTOG 0627). Neuro-Oncology. 2008;10:(abstract MA-30)
  82. Kopetz S, Wolff R, Eng C, et al. Phase IB study of Src inhibition with dasatinib in combination with 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) and cetuximab in metastatic colorectal cancer. Proc AACR. 2008;(abstract LB-69)
  83. Brooks HD, Glisson B, Lu C, et al. Phase II study of dasatinib in the treatment of head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2009;27:306s;(abstract 6022)
  84. Kluger HM, Dudek A, McCann C, et al. A phase II trial of dasatinib in advanced melanoma. J Clin Oncol. 2009;27:463s;(abstract 9010)
  85. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. Inhibition of SRC tyrosine kinase impairs inherent and acquired gemcitabine resistance in human pancreatic adenocarcinoma cells. Clin Cancer Res. 2004;10:2307–2318
  86. Yu EY, Wilding G, Posadas E, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2009;15:7421–7428
  87. Wildes TM, Procknow E, Weilbaecher K, Vij R. Effect of dasatinib on bone metabolism in multiple myeloma. J Clin Oncol. 2008;26:471s;(abstract 8568)
  88. Woodman SE, Trent JC, Stemke-Hale K, et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther. 2009;8:2079–2085

PII: S0305-7372(10)00035-6

doi: 10.1016/j.ctrv.2010.02.015

Cancer Treatment Reviews
Volume 36, Issue 6 , Pages 492-500 , October 2010