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Erschienen in: Breast Cancer Research and Treatment 2/2011

01.07.2011 | Preclinical study

Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2011

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Abstract

Trastuzumab (Herceptin®) is currently used as a treatment for patients whose breast tumors overexpress HER2/ErbB2. Trastuzumab-DM1 (T-DM1, trastuzumab emtansine) is designed to combine the clinical benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine derivative). Currently T-DM1 is being tested in multiple clinical trials. The mechanisms of action for trastuzumab include inhibition of PI3K/AKT signaling pathway, inhibition of HER-2 shedding and Fcγ receptor mediated engagement of immune cells, which may result in antibody-dependent cellular cytotoxicity (ADCC). Here we report that T-DM1 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors.
Literatur
1.
Zurück zum Zitat Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRef Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRef
2.
Zurück zum Zitat Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182PubMedCrossRef Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182PubMedCrossRef
3.
Zurück zum Zitat Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712PubMedCrossRef Slamon DJ, Godolphin W, Jones LA et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712PubMedCrossRef
4.
Zurück zum Zitat Carter P, Presta L, Gorman CM et al (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89:4285–4289PubMedCrossRef Carter P, Presta L, Gorman CM et al (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89:4285–4289PubMedCrossRef
5.
Zurück zum Zitat Cho HS, Mason K, Ramyar KX et al (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421:756–760PubMedCrossRef Cho HS, Mason K, Ramyar KX et al (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421:756–760PubMedCrossRef
6.
Zurück zum Zitat Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672PubMedCrossRef Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672PubMedCrossRef
7.
Zurück zum Zitat Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRef Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684PubMedCrossRef
8.
Zurück zum Zitat Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRef Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRef
9.
Zurück zum Zitat Joensuu H, Kellokumpu-Lehtinen PL, Bono P et al (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809–820PubMedCrossRef Joensuu H, Kellokumpu-Lehtinen PL, Bono P et al (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809–820PubMedCrossRef
10.
Zurück zum Zitat Sliwkowski MX, Lofgren J, Lewis GD, Hotaling TE, Fendly BM, Fox JA (1999) Nonclinical studies addressing the mechanism of action of Herceptin® (Trastuzumab). Semin Oncol 26(Suppl 12):60–70PubMed Sliwkowski MX, Lofgren J, Lewis GD, Hotaling TE, Fendly BM, Fox JA (1999) Nonclinical studies addressing the mechanism of action of Herceptin® (Trastuzumab). Semin Oncol 26(Suppl 12):60–70PubMed
11.
Zurück zum Zitat Junttila TT, Akita RW, Parsons K et al (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15:429–440PubMedCrossRef Junttila TT, Akita RW, Parsons K et al (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15:429–440PubMedCrossRef
12.
Zurück zum Zitat Lewis GD, Figari I, Fendly B et al (1993) Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 37:255–263PubMedCrossRef Lewis GD, Figari I, Fendly B et al (1993) Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 37:255–263PubMedCrossRef
13.
Zurück zum Zitat Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6:443–446PubMedCrossRef Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6:443–446PubMedCrossRef
14.
Zurück zum Zitat Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRef Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRef
15.
Zurück zum Zitat Lewis Phillips GD, Li G, Dugger DL et al (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68:9280–9290PubMedCrossRef Lewis Phillips GD, Li G, Dugger DL et al (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68:9280–9290PubMedCrossRef
16.
Zurück zum Zitat Chari RV, Martell BA, Gross JL et al (1992) Immunoconjugates containing novel maytansinoids: promising anticancer drugs. Cancer Res 52:127–131PubMed Chari RV, Martell BA, Gross JL et al (1992) Immunoconjugates containing novel maytansinoids: promising anticancer drugs. Cancer Res 52:127–131PubMed
17.
Zurück zum Zitat Remillard S, Rebhun LI, Howie GA, Kupchan SM (1975) Antimitotic activity of the potent tumor inhibitor maytansine. Science 189:1002–1005PubMedCrossRef Remillard S, Rebhun LI, Howie GA, Kupchan SM (1975) Antimitotic activity of the potent tumor inhibitor maytansine. Science 189:1002–1005PubMedCrossRef
19.
Zurück zum Zitat Austin CD, Wen X, Gazzard L, Nelson C, Scheller RH, Scales SJ (2005) Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates. Proc Natl Acad Sci USA 102:17987–17992PubMedCrossRef Austin CD, Wen X, Gazzard L, Nelson C, Scheller RH, Scales SJ (2005) Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates. Proc Natl Acad Sci USA 102:17987–17992PubMedCrossRef
20.
Zurück zum Zitat Krop IE, Beeram M, Modi S et al (2010) Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 28:2698–2704PubMedCrossRef Krop IE, Beeram M, Modi S et al (2010) Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 28:2698–2704PubMedCrossRef
21.
Zurück zum Zitat Kurebayashi J, Otsuki T, Tang CK et al (1999) Isolation and characterization of a new human breast cancer cell line, KPL-4, expressing the Erb B family receptors and interleukin-6. Br J Cancer 79:707–717PubMedCrossRef Kurebayashi J, Otsuki T, Tang CK et al (1999) Isolation and characterization of a new human breast cancer cell line, KPL-4, expressing the Erb B family receptors and interleukin-6. Br J Cancer 79:707–717PubMedCrossRef
22.
Zurück zum Zitat Munson PJ, Rodbard D (1980) Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 107:220–239PubMedCrossRef Munson PJ, Rodbard D (1980) Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 107:220–239PubMedCrossRef
23.
Zurück zum Zitat Idusogie EE, Presta LG, Gazzano-Santoro H et al (2000) Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc. J Immunol 164:4178–4184PubMed Idusogie EE, Presta LG, Gazzano-Santoro H et al (2000) Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc. J Immunol 164:4178–4184PubMed
24.
Zurück zum Zitat Sias PE, Kotts CE, Vetterlein D, Shepard M, Wong WL (1990) ELISA for quantitation of the extracellular domain of p185HER2 in biological fluids. J Immunol Methods 132:73–80PubMedCrossRef Sias PE, Kotts CE, Vetterlein D, Shepard M, Wong WL (1990) ELISA for quantitation of the extracellular domain of p185HER2 in biological fluids. J Immunol Methods 132:73–80PubMedCrossRef
25.
Zurück zum Zitat Finkle D, Quan ZR, Asghari V et al (2004) HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice. Clin Cancer Res 10:2499–2511PubMedCrossRef Finkle D, Quan ZR, Asghari V et al (2004) HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice. Clin Cancer Res 10:2499–2511PubMedCrossRef
26.
Zurück zum Zitat Erickson HK, Park PU, Widdison WC et al (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 66:4426–4433PubMedCrossRef Erickson HK, Park PU, Widdison WC et al (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 66:4426–4433PubMedCrossRef
27.
Zurück zum Zitat Musolino A, Naldi N, Bortesi B et al (2008) Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 26:1789–1796PubMedCrossRef Musolino A, Naldi N, Bortesi B et al (2008) Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 26:1789–1796PubMedCrossRef
28.
Zurück zum Zitat Shields RL, Namenuk AK, Hong K et al (2001) High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem 276:6591–6604PubMedCrossRef Shields RL, Namenuk AK, Hong K et al (2001) High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem 276:6591–6604PubMedCrossRef
29.
Zurück zum Zitat Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL (2002) Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62:4132–4141PubMed Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL (2002) Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62:4132–4141PubMed
30.
Zurück zum Zitat Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J (2001) Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res 61:4744–4749PubMed Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J (2001) Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res 61:4744–4749PubMed
31.
Zurück zum Zitat Eichhorn PJ, Gili M, Scaltriti M et al (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221–9230PubMedCrossRef Eichhorn PJ, Gili M, Scaltriti M et al (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221–9230PubMedCrossRef
32.
Zurück zum Zitat Nagata Y, Lan KH, Zhou X et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–127PubMedCrossRef Nagata Y, Lan KH, Zhou X et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6:117–127PubMedCrossRef
34.
Zurück zum Zitat Smith I, Procter M, Gelber RD et al (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369:29–36PubMedCrossRef Smith I, Procter M, Gelber RD et al (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369:29–36PubMedCrossRef
Metadaten
Titel
Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer
Publikationsdatum
01.07.2011
Erschienen in
Breast Cancer Research and Treatment / Ausgabe 2/2011
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-010-1090-x

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