Chapter 6. Discussion

6.4 Conclusions

Triple negative breast cancer is still a highly unmet medical need and therefore target selection and preclinical testing are needed to provide rational drug


combinations for clinical testing. Based on our in vitro evaluation of a range of inhibitors:

dasatinib and rapamycin are active and therefore warrant further investigation in triple negative breast cancer.

protein levels of EPHA2, CAV1 and CAV2 appear to be useful biomarkers of dasatinib response.

the combination of dasatinib and cisplatin exhibited synergy in inhibiting growth of triple negative cell lines.

Future clinical trials combining dasatinib with cisplatin and testing the validity of EPHA2, CAV1 and CAV2 as predictive biomarkers may thus be warranted in patients with advanced triple negative breast cancer.



1. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. Slamon, D and al., et. 11, 2001, N Engl J Med, Vol. 344, pp. 783-92.

2. Dinstinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms. Sorlie, T, et al. 127, 2006, BMC Genomics, Vol. 7.

3. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Prat, A, et al. R68, 2010, Breast Cancer Research, Vol. 12.

4. Molecular portraits of human breast tumours. Perou, C, et al. 6797, 2000, Nature, Vol. 406, pp. 747-752.

5. Molecular Stratification of Triple-Negative Breast Cancers. Perou, C. Suppl 5, 2010, The Oncologist, Vol. 15, pp. 39-48.

6. Gene expression profiling and clinicopathological characterization of triple negative/basal-like breast carcinomas. Kreike B, et al. 2007, Breast Cancer Res.

7. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Rouzier, R, et al. 2005, Clin Cancer Res, Vol. 11, pp. 5678-5685.

8. Breast cancer molecular subclassification and estrogen receptor expression to predict efficacy of adjuvant anthracyclines-based chemotherapy: a biomarker study from two randomized trials. Conforti, R and al., et. 2007, J Clin Oncol.

9. Response to neoadjuvant therapy and long-term survival in patients with triple negative breast cancer. Liedtke, C, et al. 2008, J Clin Oncol, Vol. 26, pp. 1275-1281. 10. The addition of cetuximab to cisplatin increases ORR and PFS in metastatic TNBC:Results of a randomized phase 2 study (BALI-1). Baselga, J, et al. 2010.

11. Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Corkery, Brendan, et al. 5, 2009, Annals of Oncology, Vol. 20, pp. 862- 867.

12. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. Miller, K, et al. 2007, N Engl J Med, Vol. 357, pp. 2666-2676.


13. Cisplatin chemotherapy in the treatment of BRCA1-positive metastatic breast cancer. Byrski, T, et al. Orlando : s.n., 2009. ASCO Annual Meetinb Proceedings. 14. A randomized phase III study of iniparib (BSI-201) in combination with

gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). O'Shaughnessy, J, et al. suppl; abstr 1007, 2011, J Clin Oncol 29: 2011 (suppl; abstr 1007), Vol. 29.

15. Dasatinib as a Single Agent on Triple-Negative Breast Cancer: Results of an Open- Label Phase 2 Study. Finn, Richard, et al. 21, 2011, Clin Cancer Res, Vol. 17, pp. 6905- 13.

16. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Nielsen, T, et al. 2004, Clin Cancer Res, Vol. 10, pp. 5367- 5374.

17. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. Tischkowitz, M, et al. 2007, BMC Cancer, Vol. 7, p. 134.

18. Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Corkery, B, et al. 2009, Ann Oncol.

19. Repeated observation of breast tumor subtypes in independent gene expression data sets. Sorlie, T, et al. 2003, Proc Natl Acad Sci USA, Vol. 100, pp. 8418-8423. 20. Hallmarks of "BRCAness" in sporadic cancers. Turner, N, Tutt, A and Ashworth, A. 2004, Nat Rev Cancer, Vol. 4, pp. 814-819.

21. Inhibition of poly(ADP)-ribose polymerase as a therapeutic strategy for breast cancer. Comen, E and Robson, M. 2010, Oncology (Williston Park), Vol. 24, pp. 55-62. 22. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Farmer, H, et al. 2005, Nature, Vol. 434, pp. 917-921.

23. Phase II trial of oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. Tutt, A, et al. 18 suppl, 2009, J Clin Oncol, Vol. 27, p. Abstracr CRA501. 24. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. O'Shaughnessy, J, et al. 3, 2011, N Engl J Med, Vol. 364, pp. 205-14.

25. A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer. Modi, S, et al. 2005, Breast Cancer Res Treat, Vol. 90, pp. 157-163.


26. A Renaissance for SRC. Yeatman, T. 2004, Nat Rev Cancer, Vol. 4, pp. 470-480.

27. Targeting Src in breast cancer. Finn, R. 2008, Ann Oncol, Vol. 19, pp. 1379-1386.

28. Cellular functions regulated by Src family kinases. Thomas, S and Brugge, J. 1997, Annu Rev Cell Dev Biol, Vol. 13, pp. 513-609.

29. Src kinase regulation by phosphorylation and dephosphorylation. Roskoski, R. 2005, Biochom Biophys Res Commun, Vol. 331, pp. 1-14.

30. Src inhibitor dasatinib inhibits growth of breast cancer cells by modulating EGFR signaling. Nautiyal, J, et al. 2009, Cancer Letters, Vol. 283, pp. 143-151.

31. Src kinase becomes preferentially associated with the VEGFR, KDR/Flk-1, following VEGF stimulation of vascular endothelial cells. Chou, M, Wang, J and Fujita, D. 2002, BMC Biochem, Vol. 3, p. 32.

32. EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Palmer, A, et al. 2002, Mol Cell, Vol. 9, pp. 725-737.

33. 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 grownig in vitro. Finn, Richard, et al. 2007, Breast Cancer Res Treat.

34. A Src/Abl kinase inhibitor, SKI-606, blocks breast cancer invasion, growth, and metastasis in vitro and in vivo. Jallal, Houda, et al. 4, 2007, Cancer Res, Vol. 67, pp. 1580-1588.

35. The hunting of the Src. Martin, G. 6, 2001, Nat Rev Mol Cell Biol, Vol. 2, pp. 467-75.

36. Molecular targeting: PI3 kinase pathway. Dancey, J. suppl 4, 2004, Ann Oncol, Vol. 15, pp. iv233-9.

37. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. Baselga, J, et al. 6, 2012, N Engl J Med, Vol. 366, pp. 520-9.

38. Mitogen-Activated Protein Kinases: Specific Messages from ubiquitous messengers. Schaeffer, H and Weber, M. 4, 1999, Mol and Cel Biol, Vol. 19, pp. 2435-2444.

39. Sustained activation of the mitogen-activated protein kinase pathway.A mechanism underlying receptor tyrosine kinase specificity for matrix metalloproteinase-9 induction and cell migration. McCawley, L, et al. 1999, J Biol Chem, Vol. 274, pp. 4347-4353.


40. MAPK overexpression is associated with anthracyline resistance and increased risk for recurrence in patients with triple-negative breast cancer. Eralp, Y, et al. 2008, Ann Oncol, Vol. 19, pp. 669-674.

41. High ERK Protein Expression Levels Correlate with Shorter Survival in Triple-Negative Breast Cancer Patients. Bartholomeusz, C, et al. 2012, The Oncologist, Vol. 17.

42. Genome and transcriptome sequencing in prospective refractory metastatic triple negative breast cancer uncovers therapeutic vulnerabilities. Craig, D, et al. 2012, Mol Cancer Ther, Vol. [Epub ahead of print].

43. ERBB receptors and cancer: the complexity of targeted inhibitors. Hynes, N and Lane, H. 5, 2005, Nat Rev Cancer, Vol. 5, pp. 341-54.

44. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Citri, A, Skaria, K and Yarden, Y. 1, 2003, Exp Cell Res, Vol. 284, pp. 54-65.

45. The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Yarden, Y. Suppl 4, 2001, Eur J Cancer, Vol. 37, pp. S3-8. 46. Browne, Brigid. The role of receptor tyrosine kinase signalling in HER-2-positive cells and Trastuzumab resistance in breast cancer. PhD thesis. Dublin : Dublin City University, 2008. pp. 6-9.

47. Human breast cancer:correlation of relapse and survival with amplification of the HER-2/neu oncogene. Slamon, D and al., et. 4785, 1987, Science, Vol. 235, pp. 177-182. 48. HER2/neu role in breast cancer: from a prognostic foe to a predictive friend.

Ferretti, G and al., et. 1, 2007, Curr Opin Obstet Gynecol, Vol. 19, pp. 56-62.

49. c-erbB-2 overexpression decreases the benefit of adjuvant tamoxifen in eqarly-stage breast cancer without axillary lymph node metastases. Carlomagno, C and al., et. 10, 1996, J Clin Oncol, Vol. 14, pp. 2702-8.

50. HER2 over-expression and response to different chemotherapy regimens in breast cancer. Zhang, J and Liu, Y. 1, 2008, J Zhejiang Univ Sci B, Vol. 9, pp. 5-9.

51. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. Muss, H and al., et. 18, 1994, N Engl J Med, Vol. 330, pp. 1260-6. 52. Lapatinib in breast cancer. Bilancia, D and al., et. suppl 6, 2007, Ann Oncol, Vol. 18, pp. vi26-30.


53. Phase II Study of predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 in advanced Inflammatory Breast Cancer with Lapatinib Monotherapy. Johnston, S and al., et. 2008, J Clin Oncol.

54. Effect of trastuzumab on antibody-dependent cellular cytotoxicity (ADCC) in HER2 nonamplified (non-amp) breast cancer (BC) cells. Collins, D, et al. 2010. J Clin Oncol. Vol. 28, p. 15s. Abstr 659.

55. Efficacy and safety of trastuzumab as a single agent in first line treatment of HER2- overexpressing metastatic breast cancer. Vogel, C and al., et. 3, 2002, J Clin Oncol, Vol. 20, pp. 719-726.

56. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Cobleigh, M and al., et. 9, 1999, J Clin Oncol, Vol. 17, pp. 2639-2648.

57. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. Viani, G and etal. 2007, BMC Cancer, Vol. 7, p. 153.

58. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel and epirubicin chemotherapy: results of a randomized trial in HER-2 positive operable breast cancer. Buzdar, A and al., et. 16, 2005, J Clin Oncol, Vol. 23.

59. A new anti-ErbB2 strategy in the treatment of cancer: prevention of ligand-

dependent ErbB2 receptor heterodimerization. Baselga, J. 2002, Cancer Cell, Vol. 2, pp. 93-95.

60. A phase II trial with trastuzumab and pertuzumab in patients with HER2-

overexpressed locally advanced and metastatic breast cancer. Walshe, J and al., et. 6, 2006, Clin Breast Cancer, Vol. 6, pp. 535-9.

61. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. Baselga, J, et al. 2, 2012, N Engl J Med, Vol. 366, pp. 109-19.

62. A Phase II Study of Trastuzumab-DM1 (T-DM1),a Novel HER2 Antibody–Drug Conjugate, in Patients with HER2+ Metastatic Breast Cancer who Were Previously Treated with an Anthracycline, a taxane, capecitabine, lapatinib and trastuzumab. Krop, I, et al. 29 May 2012, J Clin Oncol. epub.


63. Trastuzumab emtansine (T-DM1) vs trastuzumab plus docetaxel (H+T) in previously- untreated HER2-positive metastatic breast cancer (MBC): primary results of a

randomized, multicenter, open-label phase II study (TDM4450g/B021976). Hurvitz, S, et al. 2011, Eur J Cancer, Vol. 47 S, p. 330.

64. Trastuzumab Emtansine for HER2-positive Advanced Breast Cancer. Verma, S, et al. 2012, N Engl J Med, Vol. 367, pp. 1783-1791.

65. A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2- positive and HER2-negative advanced or metastatic breast cancer. Burstein, H, et al. 2008, Ann Oncol, Vol. 19, pp. 1068-1074.

66. Lapatinib plus capecitabine(Drug information on capecitabine) for HER2-positive advanced breast cancer. Geyer, C, et al. 2006, N Engl J Med, Vol. 355, pp. 2733-2743. 67. Randomized study of lapatinib alone or with trastuzumab in heavily pretreated ErbB2-positive MBC progressing on trastuzumab. Blackwell, K, O'Shaughnessy, J and al., et. 2010, J Clin Oncol, Vol. 28, pp. 1124-1120.

68. The effects of lapatinib and neratinib on HER2 protein levels in breast cancer cell lines. Collins, Dennis, et al. Chicago : J Clin Oncol, 2012. Vol. 30 (suppl; abstr 637). 69. The achilles heel of ErbB-2/HER2:regulation by the Hsp90 chaperone machine and potential for pharmacological intervention. Citri, A, Kochupurakkal, B and Yarden, Y. 1, 2004, Cell Cycle, Vol. 3, pp. 51-60.

70. A critical role for HSP90 in cancer cell invasion involves interaction with the

extracellular domain of HER-2. Sidera, K, et al. 4, 2008, J Biol Chem, Vol. 283, pp. 2031- 41.

71. Targeting the function of the HER2 oncogene in human cancer therapeutics. Moasser, M. 46, 2007, Oncogene, Vol. 26, pp. 6577-92.

72. Ki67 Index, HER2 Status and Prognosis of Patients with Luminal B Breast Cancer. Cheang, Maggie, et al. 2009, J Natl Cancer Inst, Vol. 101, pp. 736-750.

73. SERM's: Current status and future trends. Morrelo, K, Wurz, G and DeGregorio, M. 1, 2002, Crit Rev Oncol Hematol, Vol. 43, pp. 63-76.

74. Aromatase inhibitors in breast cancer: an overview. Altundaq, K and Ibrahim, N. 6, 2006, Oncologist, Vol. 11, pp. 553-62.


75. Clinical use of selective estrogen receptor modulators and down regulators with the main focus on breast cancer. Baumann, C and Castiglione-Gertsch, M. 6, 2009, Minerva Ginecol, Vol. 61, pp. 517-39.

76. What is the role of ovarian ablation in the management of primary and metastatic breast cancer today? Prowell, T and Davidson, N. 5, 2004, Oncologist, Vol. 9, pp. 507- 17.

77. HER2 therapy: Molecular mechanisms of trastuzumab resistance. Nahta, R and Esteva, F. 6, 2006, Breast Cancer Res, Vol. 8, p. 215.

78. Recent advances of molecular targeted agents: opportunities for imaging. Dancey, J. 6, 2003, Cancer Biol Ther, Vol. 2, pp. 601-609.

79. New developments in multitargeted therapy for patients with solid tumours. . Le Tourneau, C, Faivre, S and Raymond, E. 1, 2008, Cancer Treat Rev, Vol. 34, pp. 37-48. 80. Gene expression profiling of breast cell lines identifies potential new basal markers. Charafe-Jauffret, E, et al. 2006, Oncogene, Vol. 25, pp. 2273–2284.

81. Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class. Buchdunger, E, et al. 7, 1995, Proc Natl Acad Sci USA, Vol. 92, pp. 2558-2562.

82. Sun, L, et al. 7, 2003, J Med Chem, Vol. 46, pp. 1116-1119.

83. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-

pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. Harris, P, et al. 15, 2008, J Med Chem, Vol. 51, pp. 4632-40.

84. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. O'Hare, T, et al. 11, 2005, Cancer Res, Vol. 65, pp. 4500-5.

85. The rapamycin-binding domain of the protein kinase mammalian target of

rapamycin is a destabilizing domain. Edwards, S and Wandles, T. 18, 2007, J Biol Chem, Vol. 282, pp. 13395-13401.

86. MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Duncia, J, et al. 20, 1998, Bioorg Med Chem Lett., Vol. 8, pp. 2839- 2844.


87. Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling. Chaussade, C, et al. 3, 2007, Biochem J, Vol. 404, pp. 449-58.

88. Acid phosphatase: endpoint for in vitro toxicity tests. Martin, A and Clynes, M. A, 1991, In Vitro Cell Dev Biol, Vol. 27, pp. 183-184.

89. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Chou, T and Talalay, P. 1984, Adv Enzyme Regul., Vol. 22, pp. 27-55.

90. Analysis of drug interactions. Bijnsdorp, I, Giovannetti, E and Peters, G. 2011, Methods Mol Biol, Vol. 731, pp. 421-434.

91. Bcr-Abl kinase domain mutations, drug resistance and the road to a cure of CML. O'Hare, T, Eide, C and Deininger, M. 7, 2007, Blood, Vol. 110, pp. 2242-2249.

92. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Shor, B, et al. 8, 2008, Cancer Res, Vol. 68, pp. 2934-43.

93. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H- 1-benzopyran-4-one (LY294002. Vlachos, C, et al. 7, 1994, J Biol Chem, Vol. 269, pp. 5241-8.

94. Identification of a novel inhibitor of mitogen-activated protein kinase. Favata, M, et al. 1998, J. Biol. Chem, Vol. 273, p. 18623.

95. Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. Huang, F, et al. 5, 2007, Cancer Res, Vol. 67, pp. 2226-38.

96. An exploratory study of sunitinib in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive metastatic breast cancer. Cardoso, F, et al. 6, 2012, Breast, Vol. 21, pp. 716-23.

97. Inhibition of IGF1R activity enhances response to trastuzumab in HER-2-positive breast cancer cells. Browne, B, et al. 1, 2011, Ann Oncol, Vol. 22, pp. 68-73.

98. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to

trastuzumab but not lapatinib. O'Brien, N, et al. 6, 2010, Mol Cancer Ther, Vol. 9, pp. 1489-502.


99. ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Klos, K, et al. 2006, Cancer Res, Vol. 66, pp. 2028-2037.

100. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF- 1alphA), synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Laughner, E, et al. 2001, Mol Cell Biol, Vol. 21, pp. 3995–4004. 101. Characterization of a novel cell line established from a patient with Herceptin- resistant breast cancer. Tanner M, Kapanen AI, Junttila T, Raheem O, Grenman S, Elo J, et al. 12, 2004, Mol Cancer Ther, Vol. 3, pp. 1585-92.

102. Sunitinib. Deeks, E and Keating, G. 17, 2006, Drugs, Vol. 66, pp. 2255-66.

103. Specific Blockade of VEGF and HER2 Pathways Results in Greater Growth Inhibition of Breast Cancer Xenografts that Overexpress HER2. Le, X, et al. 23, 2008, Cell Cycle, Vol. 7, pp. 3747–3758.

104. Src: a potential target for the treatment of triple-negative breast cancer. Tryfonopoulos D, Walsh S, Collins DM, Flanagan L, Quinn C, Corkery B, McDermott EW, Evoy D, Pierce A, O'Donovan N, Crown J, Duffy MJ. 10, 2011, Ann Oncol, Vol. 22, pp. 2234-40.

105. Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells. Pichot, CS, et al. 1, 2009, Br J Cancer, Vol. 101, pp. 38-47.

106. EphA2 overexpression causes tumorigenesis of mammary epithelial ells. Zelinski, Daniel, et al. 2001, Cancer Research, Vol. 61, pp. 2301-2306.

107. EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Ireton, Renee and Chen, Jin. 2005, Current Cancer Drug Targets, Vol. 5, pp. 149-157. 108. The ephrin-A1ligand and its receptor, EphA2, are expressed during tumor

neovascularization. Ogawa, Kazushige, et al. 2000, Oncogene, Vol. 19, pp. 6043-6052. 109. Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Pinilla, S, et al. 1, 2006, Breast Can Res Treat, Vol. 99, pp. 85- 90.

110. Gene expression profiling of breast cancer cell lines identifies potential new basal markers. Charafe-Jauffret, E, et al. 15, 2006, Oncogene, Vol. 25, pp. 2273-2284.


111. Effects of Src kinase inhibition induced by dasatinib in non-small cell lung cancer cell lines treated with cisplatin. Ceppi P, Papotti M, Monica V, Iacono ML, Saviozzi S, Pautasso M, et al. 2009, Mol Cancer Ther.

112. Identification of potential biomarkers for measuring inhibition of Src kinase activity in colon cancer cells following treatment with dasatinib. Serrels A, Macpherson IR, Evans TR, Lee FY, Clark EA, Sansom OJ, et al. 12, 2006, Mol Cancer Ther, Vol. 5, pp. 3014-22.

113. Activity of the multikinase inhibitor dasatinib against ovarian cancer cells. Konecny GE, Glas R, Dering J, Manivong K, Qi J, Finn RS, et al. 2009, Br J Cancer.

114. Role of Src expression and activation in human caner. Irby, Rosalyn and Yeatman, Timothy. 2000, Oncogene, Vol. 19, pp. 5636-5642.

115. Phase II Trial of Dasatinib in Triple-negative Breast Cancer: Results of Study CA180059. Finn, Richard, et al. 2008. SABC Proceedings.

116. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Farmer, H, et al. 2005, Nature, Vol. 434, pp. 917-21.

117. Dasatinib Plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy Data from Phase 1 Study CA180-004. J. Cortes, J. Specht, W. Gradishar, L. Strauss, A. Rybicki, X. Wu, L. Vahdat, L. Paz-Ares and G. Somlo. 24(Supl3), 2009, Cancer Res, Vol. 69, p. 3092.

118. Synergistic activity of the Src family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Kopetz, Scott, et al. 9, 2009, Cancer Research, Vol. 69, pp. 3842-49.

119. Identification and validation of phospho-SRC, a novel and potential

pharmacodynamic biomarker for dasatinib (SPRYCEL), a multi-targeted kinase inhibitor. Luo, F, et al. 2008, Cancer Chemother Pharmacol, Vol. 62, pp. 1065-1074.

120. Validation of PDGFRbeta and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib. Coluccia, A, et al. 2008, Blood, Vol. 112, pp. 1346-1356.

121. PIK3CA mutations correlate with hormone receptors, node metastasis and ERBB2

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