Novel anticancer targets: Revisiting ERBB2 and discovering ERBB3

Nature Reviews Cancer

Volumn 9, Issue 7, 2009, Pages 463-475

  Baselga, José ^a   Swain, Sandra M ^b  

^a VALL D HEBRON UNIVERSITY HOSPITAL   (Spain)

^b WASHINGTON CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [3 CHLORO 4 (2 PYRIDINYLMETHOXY)ANILINO] 3 CYANO 6 (4 DIMETHYLAMINOCROTONAMIDO) 7 ETHOXYQUINOLINE; AMG 888; ANTHRACYCLINE; ANTINEOPLASTIC AGENT; ARRY 334543; BIBW 2992; BO 18255; CAPECITABINE; DOCETAXEL; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPIDERMAL GROWTH FACTOR RECEPTOR 3; ERTUMAXOMAB; GEMCITABINE; LAPATINIB; MONOCLONAL ANTIBODY; PERTUZUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN TYROSINE KINASE INHIBITOR; T DM1; TANESPIMYCIN; TANESPIMYCIN HYDROQUINONE; TAXANE DERIVATIVE; TRASTUZUMAB; TRASTUZUMAB DM1; U 3 1287; UNCLASSIFIED DRUG;

ADD ON THERAPY; ADJUVANT THERAPY; ANTIBODY SPECIFICITY; ANTINEOPLASTIC ACTIVITY; BREAST CANCER; BREAST CARCINOMA; BREAST TUMOR; CANCER CELL CULTURE; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER MODEL; CANCER PATIENT; CANCER RESISTANCE; CANCER SURVIVAL; CARCINOGENESIS; CENTRAL NERVOUS SYSTEM METASTASIS; CLINICAL TRIAL; COLORECTAL ADENOMA; COLORECTAL CANCER; COLORECTAL CARCINOMA; DIMERIZATION; DRUG CONJUGATION; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG RECEPTOR BINDING; DRUG SAFETY; ENZYME ACTIVITY; ENZYME INHIBITION; ESOPHAGUS CANCER; GENE MUTATION; GENE OVEREXPRESSION; HEAD AND NECK CANCER; HEART DISEASE; HEART LEFT VENTRICLE EJECTION FRACTION; HUMAN; KIDNEY CANCER; LUNG CANCER; LUNG NON SMALL CELL CANCER; MELANOMA; MONOTHERAPY; MULTIPLE MYELOMA; NONHUMAN; ONCOGENE; OVARY CANCER; PANCREAS CANCER; PERITONEUM CANCER; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; RECEPTOR BLOCKING; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; STOMACH CANCER; TREATMENT OUTCOME; TREATMENT RESPONSE; TUMOR XENOGRAFT; UTERINE TUBE CARCINOMA;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANTIBODIES, MONOCLONAL; DIMERIZATION; FEMALE; HSP90 HEAT-SHOCK PROTEINS; HUMANS; MALE; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; RECEPTOR, ERBB-2; RECEPTOR, ERBB-3; SIGNAL TRANSDUCTION;

EID: 67649472398     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc2656     Document Type: Review

References (144)

1. Hynes, N. E. & Lane, H. A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Rev. Cancer 5, 341-354(2005).
2. Mendelsohn, J. & Baselga, J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J. Clin. Oncol. 21, 2787-2799 (2003).
3. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127-137 (2001).
4. Olayioye, M. A., Neve, R. M., Lane, H. A. & Hynes, N. E. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 19, 3159-3167 (2000).
5. Ferguson, K. M. et al. EGFactivates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol. Cell 11, 507-517 (2003).
6. Cho, H. S. et al. Structure of the extracellular region of HER3 reveals an interdomain tether. Science 297, 1330-1333 (2002).
7. Burgess, A. W. et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 12, 541-552 (2003).
8. Ogiso, H. et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775-787 (2002).
9. Zhang, X., Gureasko, J., Shen, K., Cole, P. A. & Kuriyan, J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137-1149 (2006).
10. Jeffrey, P. D. et al. The crystal structure of human cyclin H. Nature 376, 313-320(1995).
11. Hubbard, S. R. EGF receptor activation: push comes to shove. Cell 125, 1029-1031 (2006).
12. Sierke, S. L, Cheng, K., Kim, H. H. & Koland, J. G. Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein. Biochem. J. 322, 757-763 (1997).
13. Garrett, T. P. et al. The crystal structure of truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cell 11,495-505(2003).
14. Berger, M. B., Mendrola, J. M. & Lemmon, M. A. ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FESS Lett. 569, 332-336 (2004).
15. Feng, S. M. et al. The HER4 cytoplasmic domain, but not its C-terminus, inhibits mammary cell proliferation. Mol. Endocrinol. 21, 1861-1876(2007).
16. Tzahar, E. et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol. Cell. Biol. 16, 5276-5287 (1996).
17. Pinkas-Kramarski, R. et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBOJ. 15,2452-2467(1996).
18. Hsieh, A. C. & Moasser, M. M. Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br. J. Cancer 97, 453-457 (2007).
19. Lee-Hoeflich, S. T. et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 68, 5878-5887 (2008).
20. Slamon, D.J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177-182 (1987).
21. Owens, M. A. et al. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin. Breast Cancer 5, 63-69 (2004).
22. Yaziji, H. et al. HER-2 testing in breast cancer using parallel tissue-based methods. J. Am. Med. Assoc. 291, 1972-1977 (2004).
23. Vermeij, J. et al. Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers. BMC Cancer 8, 3 (2008).
24. Jaehne, J. et al. Expression of Her2/neu oncogene product p 185 in correlation to clinicopathological and prognostic factors of gastric carcinoma. J. Cancer Res. Clin. Oncol. 118, 474-479 (1992).
25. Cornolti, G. et al. Amplification and overexpression of HER2/net/gene and HER2/neu protein in salivary duct carcinoma of the parotid gland. Arch. Otolaryngol. Head Neck Surg. 133, 1031-1036(2007).
26. Zuo, T. et al. FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2IErbB2 oncogene. Cell 129, 1275-1286 (2007).
27. Liu, E. et al. The HER2 (c-erbB-2) oncogene is frequently amplified in in situ carcinomas of the breast. Oncogene 7, 1027-1032 (1992).
28. Park, K., Han, S., Kim, H. J., Kim, J. & Shin, E. HER2 status in pure ductal carcinoma in situ and in the intraductal and invasive components of invasive ductal carcinoma determined by fluorescence in situ hybridization and immunohistochemistry. Histopathoiogy 8, 702-707 (2006).
29. Cappuzzo, F., Bemis, L & Varella-Garcia, M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N. Engl. J. Med. 354, 2619-2621 (2006).
30. Wang, S. E. et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10, 25-38(2006).
31. Holbro,T. et al. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc. Natl Acad. Sci. USA 100, 8933-8938 (2003).
32. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655-1657(2002).
33. Prigent, S. A. & Gullick, W. J. Identification of c-erbB-3 binding sites for phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBOJ. 13, 2831-2841 (1994).
34. Soltoff, S. P., Carraway, K. L. 3rd, Prigent, S. A., Gullick, W. G. & Cantley, L. C. ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. MoL. Cell. Biol. 14, 3550-3558(1994).
35. Hellyer, N. J., Cheng, K. & Koland, J. G. ErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem. J. 333, 757-763 (1998).
36. Sergina, N. V. et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445, 437-441 (2007).
37. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039-1043 (2007).
38. Wheeler, D. L. et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 27, 3944-3956 (2008).
39. Bobrow, L. G., Millis, R. R., Happerfield, L. C. & Gullick, W. J. c-erbB-3 protein expression in ductal carcinoma in situ of the breast. Eur. J. Cancer 33, 1846-1850 (1997).
40. Quinn, C. M. et al. C-erbB-3 protein expression in human breast cancer: comparison with other tumor variables and survival. Histopathology 25, 247-252 (1994).
41. Travis, A. et al. C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br. J. Cancer 74, 229-233 (1996).
42. Siegel, P. M., Ryan, E. D., Cardiff, R. D. & Muller, W. J. Elevated expression of activated forms of Neu/ ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBOJ. 18, 2149-2164 (1999).
43. Atlas, E. et al. Heregulin is sufficient for the promotion of tumorigen ¡city and metastasis of breast cancer cells in vivo. Mol. Cancer Res. 1, 165-175(2003).
44. Krane, I. M. & Leder, P. NDF/heregulin induces persistence of terminal end buds and adenocarcinomas in the mammary glands of transgenic mice. Oncogene 12, 1781 -1788 (1996).
45. Tsai, M. S., Shamon-Taylor, L. A., Mehmi, I., Tang, C. K. & Lupu, R. Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer. Oncogene 22, 761-768(2003).
46. Rajkumar, T, Stamp, G. W., Hughes, C. M. & Gullick, W. J. C-erbB3 protein expression in ovarian cancer. Clin. Mol. Pathol. 49, M199-M202 (1996).
47. Tanner, B. et al. ErbB-3 predicts survival in ovarian cancer. J. Clin. Oncol. 24, 431 7-4323 (2006).
48. Campiglio, M., Ali, S., Knyazev, P. G. & Ullrich, A. Characteristics of EGFR family-mediated HRG signals in human ovarian cancer. J. Cell. Biochem. 73, 522-532 (1999).
49. Engelman, J. A. et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancers cell lines. Proc. Natl Acad. Sci. USA 102, 3788-3793 (2005).
50. Gregory, C. W. et al. Heregulin-induced activation of HER2 and HER3 increases androgen receptor transaetivation and CWR-RI human recurrent prostate cancer cell growth. Clin. Cancer Res. 111 704-1712 (2005).
51. Mellinghoff, I. K. et al. HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer Cell 6, 517-527 (2004).
52. Hudziak, R. M. et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol. Cell. Biol. 9, 1165-1173 (1989).
53. Baselga, J. et al. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 58, 2825-2831 (1998).
54. Moody, S. E. et al. Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell 2, 451-461 (2002).
55. Ursini-Siegel, J. et al. Insights from transgenic mouse models of ERBB2-induced breast cancer. Nature Rev. Cancer 7, 389-397 (2007).
56. Hirata, A. et al. HER2 ove rex press increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells. Cancer Res. 65, 4253-4260 (2005).
57. Ritter, C.A. et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin. Cancer Res. 13, 4909-491 9 (2007).
58. Gril, B. et al. Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J. Natl. Cancer Inst. 100, 1092-1103(2008).
59. Drebin, J. A. et al. Monoclonal antibodies reactive with distinct domains of the neu oncogene-encoded pi 85 molecular exert synergistic anti-tumor effects in vivo. Oncogene 2, 273-277 (1 988).
60. Carter, P. et al. Humanization of an anti-pi 85HER2 antibody for human cancer therapy. Proc. Natl Acad. Sci. USA 89, 4285-4289 (1 992).
61. Cho, H. S. et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421, 756-760 (2003).
62. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumor biology: Herceptin acts as an anti-angiogenic cocktail. Nature 416, 279-280 (2002).
63. Lane, H. A. et al. ErbB2 potentiates breast tumor proliferation through modulation of p27Kipl-Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol. Cell. Biol. 20, 3210-3223(2000).
64. Kipl in anti-HER2 antibody-induced G 1 cell cycle arrest and tumor growth inhibition. J. Biol. Chem. 278, 23441-23450 (2003).
65. Longva, K. E., Pedersen, N. M., Haslekås, C, Stang, E. & Madshus, I. H. Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2. Int. J. Cancer 116, 359-367 (2005).
66. Nagata, Y et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6, 117-127(2004).
67. Cuello. M. et al. Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res. 61, 4892-4900 (2001).
68. Le, X. et al. Anti-HER2 antibody trastuzumab inhibits CDK2-mediated nPAt and histone H4 expression via the PI3K pathway. Cell Cycle 5, 1654-1661 (2006).
69. Berns, K. et al. Afunctional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12,395-402(2007).
70. Eichhorn, P. J. et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 68, 9221-9230 (2008).
71. Wehrman, T S. et al. A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactions. Proc. Natl Acad. Sci. USA 103, 19063-19068(2006).
72. Clynes, R. A., Towers, T. L, Presta, L G. & Ravetch, J. V Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nature Med. 6, 443-446 (2000).
73. Musolino, A. et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/ net/-positive metastatic breast cancer. J. Clin. Oncol. 26, 1789-1796(2008).
74. Molina, M. A. et al. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 61, 4744-4749 (2001).
75. Baselga, J. et al. Phase II study of weekly intravenous recombinant humanized anti-pi 85HER2 monoclonal antibody in patients with HER2/net/-overexpressing metastatic breast cancer. J. Clin. Oncol. 14, 737-744 (1996).
76. Cobleigh, M. A. et al. Multinational study of the efficacy and safety of humanized anti-HER2 antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic breast disease. J. Clin. Oncol. 17, 2639-2648(1999).
77. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783-792 (2001).
78. Marty, M. et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J. Clin. Oncol. 23, 4265-4274 (2005).
79. Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673-1684(2005).
80. Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659-1672(2005).
81. Joensuu, H. et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N. Engl. J. Med. 354, 809-820 (2006).
82. Smith, I. et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369, 29-36(2007).
83. Mohsin, S. K. et al. Neoadjuvant trastuzumab induces apoptosis in primary breast cancers. J. Clin. Oncol. 23,2460-2468(2005).
84. Lazaridis, G., Pentheroudakis G. & Pavlidis N. Integrating trastuzumab in the neoadjuvant treatment of primary breast cancer: Accumulating evidence of efficacy, synergy and safety. Crit. Rev. Oncol. Hematol. 66,31-41 (2008).
85. Franklin, M. C. et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5, 317-328(2004).
86. Hubbard, S. R. EGF receptor inhibition: attacks on multiple fronts. Cancer Cell 7 287-288 (2005).
87. Fendly, B. M. et al. Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/net/ gene product. Cancer Res. 50, 1550-1558(1990).
88. Sliwkowski, M. X. et al. Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J. Biol. Chem. 269, 14661-14665 (1994).
89. Lewis, G. D. et al. Differential responses of human tumor cell lines to anti-pi 85HER2 monoclonal antibodies. Cancer Immunol. Immunother. 37, 255-263 (1993).
90. Schaefer, G., Fitzpatrick, V D. & Sliwkowski, M. X. y-Heregulin: a novel heregulin isoform that is;an autocrine growth factor for the human breast tumor cell line, MDA-MB-I 75. Oncogene 15, 1385-1394 (1997).
91. Fitzpatrick, V. D., Pisacane, P. I., Vandlen, R. L & Sliwkowski, M. X. Formation of a high affinity heregulin binding site using the soluble extracellular domains of ErbB2 with ErbB3 or ErbB4. FEBS Lett. 431, 102-106(1998).
92. Mendoza, N., Philips, G. L, Silva, J., Schwall, R. & Wickramasinghe, D. Inhibition of ligand-mediated HER2 activation in androgen-independent prostate cancer. Cancer Res. 62, 5485-5488 (2002).
93. Agus, D. B. et al. Targeting ligand activated ErbB2 signaling inhibits breast and prostate tumor growth. CancerCell2, 127-137 (2002).
94. Baselga, J. A new anti-ErbB2 strategy in the treatment of cancer: prevention of ligand-dependent ErbB2 receptor heterodimerization. Cancer Cell 2, 93-95 (2002).
95. Arteaga, C. L. et al. A phase I-ll study of combined blockade of the ErbB receptor network with trastuzumab and gefitinib in patients with HER2 (ErbB2)-overexpressing metastatic breast cancer. Clin. Cancer Res. 14, 6277-6283 (2008).
96. Mullen, P., Cameron, D. A., Hasmann, M., Smyth, J. F & Langdon, S. P. Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling. Mol. Cancer Ther. 6, 93-100 (2007).
97. Sakai, K. et al. Pertuzumab, a novel dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway. Cancer Sci. 98, 1498-1503(2007).
98. Mann, M. et al. Targeting cyclooxygenase 2 and HER-2/net/ pathways inhibits colorectal carcinoma growth. Gastroenterology 120, 1713-1719 (2001).
99. Cortes, J. et al. Open label, randomized, phase II study of pertuzumab (P) in patients (pts) with metastatic breast cancer (MBC) with low expression of HER2. J. Clin. Oncol. 23 (Suppl.), 3068 (2005).
100. Nahta, R., Hung, M. C. & Esteva, F. J. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 64, 2343-2346 (2004).
101. Spiridon, C. I. et al. Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo. Clin. Cancer Res. 8, 1720-1730 (2002).
102. 2 fragments of a mixture of three monoclonal anti-Her-2 antibodies. Clin. Cancer Res. 10, 3542-3551 (2004).
103. Portera, C. C. et al. Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with human epidermal growth factor receptor 2positive metastatic breast cancer. Clin. Cancer Res. 14,2710-2716(2008).
104. Baselga, J. et al. Objective response rate in a phase II multicenter trial of pertuzumab, a HER2 dimerization inhibiting monoclonal antibody in combination with trastuzumab in patients with HER2-positive metastatic breast cancer which has progressed during treatment with trastuzumab. J. Clin. Oncol. 25 (Suppl.), 1004 (2007).
105. Gelmon, K. A. et al. Results of a Phase II trial of trastuzumab (H) and pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy. J. Clin. Oncol. 26 (Suppl.), 1026 (2008).
106. Burris, H. A. et al. A phase II study of trastuzumabDM 1 (T-DMI), aHER2 antibody-drug conjugate (ADC), in patients (pts) with HER2 + metastatic breast cancer (MBC). The American Society for Clinical Oncology [online]. http://www.asco.org/ASCO/ Abstracts + %26 + Virtual + Meeting/ Abstracts? &vmvview=abst detail view&confID = 58&abstractID=40302(2008).
107. O'Shaughnessy, J. et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2 + metastatic breast cancer progressing on trastuzumab therapy. J. Clin. Oncol. 26 (Suppl.), 1015 (2008).
108. Makhija, S. et al. Results from a Phase IIrandomized, placebo-controlled, double-blind trial suggest improved PFS with the addition of pertuzumab to gemcitabine in patients with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer. J. Clin. Oncol. 25 (Suppl.), 5507 (2007).
109. Makhija, S. et al. HER3 pathway gene expression analysis in a Phase Il study of pertuzumab + gemcitabine vs. gemcitabine + placebo in patients with platinum-resistant epithelial ovarian cancer. J. Clin. Oncol. 26 (Suppl.), 4483 (2008).
110. Amler, L. et al. in Proceedings of the 99th Annual Meeting of the American Association for Cancer Research, Abstract Number 4483 (San Diego, California, 2008).
111. Negro, A. et al. erbB2 is required for G proteincoupled receptor signaling in the heart. Proc. Natl Acad. Sci. USA 103, 15889-15893 (2006).
112. Kiewe, P. et al. Phase I trial of the trif unctional antiHER2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer. Clin. Cancer Res. 12, 3085-3091 (2006).
113. Lewis Phillips, G. D. et al. Targeting HER2-positive breast cancer with trastuzumab-DM 1, an antibody-cytotoxic drug conjugate. Cancer Res. 68, 9280-9290 (2008).
114. Austin, C. D. et al. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Moi. Biol. Cell 15, 5268-5282(2004).
115. Spector, N. L. et al. A study of the biological effects of lapatinib (GW57201 6), a reversible inhibitor of ErbBI and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J. Clin. Oncol. 23, 2502-2512 (2005).
116. Geyer, C. E. et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355, 2733-2743 (2006).
117. Lin, N. U. et al. EGF 105084, a phase II study of lapatinib for brain metastases in patients (pts) with Her2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy. J. Clin. Oncol. 25 (Suppl.), 1112 (2007).
118. Pedersen, K. et al. A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis. Moi. Cell. Biol. 13 Apr 2009 (doi:0:MCB.01803-08v1).
119. Scaltriti, M. et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J. Natl Cancer Inst. 99, 628-638 (2007).
120. Konecny, G. E. et al. Activity of the dual kinase inhibitor lapatinib (GW57201 6) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 66, 1630-1639(2006).
121. Scaltriti, M. et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene 28, 803 - 814 (2009).
122. Burstein, H. J. et al. in 31st San Antonio Breast Cancer Symposium, Abstract Number 37 (San Antonio, Texas, 2008).
123. Li, D. et al. BIBW2992,an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27, 4702-4711 (2008).
124. Eskens, F. A. et al. A Phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumors. Br. J. Cancer 98, 80-85 (2008).
125. Freeman, D., Ogbagabriel, S., Rothe, M., Radinsky, R. & Treder, M. in Proceedings of the 99th Annual Meeting of the American Association for Cancer Research, Abstract Number LB-21 (San Diego, California, 2008).
126. Citri, A., Kochupurakkal, B. S. & Yarden, Y. The achules heel of ErbB-2/HER2: regulation of the Hsp90 chaperone machine and potential for pharmacological intervention. Cell Cycle 3, 51-60 (2004).
127. Citri, A. et al. Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. EMBOJ. 21, 2407-2417(2002).
128. Mimnaugh, E. G., Chavany, C. & Neckers, L Polyubiquitination and proteasomal degradation of the pi 185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J. Biol. Chem. 271, 22796-22801 (1996).
129. Munster, P. N., Marchion, D. C, Basso, A. D. & Rosen, N. Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway. Cancer Res. 62, 3132-3137 (2002).
130. Modi, S. et al. Phase II trial of the Hsp90 inhibitor tanespimycin (Tan) + trastuzumab (T) in patients (pts) with HER2 positive metastatic breast cancer (MBC). J. Clin. Oncol. 26 (Suppl.), 1027 (2008).
131. Weinstein, I., B. & Joe, A. Oncogene addiction. Cancer Res. 68, 3077-3078 (2008).
132. Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1 -dependent pathways. Nature Med. 10, 594-601 (2004).
133. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sei. USA. 98, 10314-10319 (2001).
134. Steelman, L S. et al. Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors. Oncogene 27, 4086-4095 (2008).
135. Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Rev. Genetics 7, 606-619 (2006).
136. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nature Rev. Cancer 2, 489-501 (2002).
137. Yuan, T. L. & Cantley, L. C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 27, 5497-5510 (2008).
138. Fruman, D. A., Meyers, R. E. & Cantley, L. C. Phosphoinositide kinases. Annu. Rev. Biochem. 67, 481-507 (1998).
139. Gordon, M. S. et al. Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J. Clin. Oncol. 4, 4324-4332 (2006).
140. Herbst, R. S. et al. Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non small cell lung cancer. Clin. Cancer Res. 13,6175-6181 (2007).
141. de Bono, J. S. et al. Open-label Phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J. Clin. Oncol. 25, 257-262 (2007).
142. Agus, D. B. et al. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J. Clin. Oncol. 23, 2534-2543 (2005).
143. Modi, S. et al. Combination of trastuzumab and tanespimycin (1 7-AAG, KOS-953) is safe and active in trastu zu m ab-refractory HER2-over expressing breast cancer: a phase I dose-escalation study. J. Clin. Oncol. 25,5410-5417(2007).
144. Miller, K. et al. Phase I trial of alvespimycin (KOS-1022; 1 7-DMAG) and trastuzumab (T). J. Clin. Oncol. 25 (Suppl.), 1115 (2007).