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Lani · 08-03-2008, 06:08 AM

I was told the article is to come out soon in ONCOGENE

Home > Abstracts & Virtual Meeting > Abstracts > 2008 ASCO Annual Meeting

Effect of lapatinib on accumulation of inactive HER2 at the cell membrane and on antibody-dependent cellular cytotoxicity (ADCC) mediated by trastuzumab: A novel mechanism for the enhanced effects of combined anti-HER2 therapy.
Sub-category:
Tyrosine Kinase Inhibitors
Category:
Developmental Therapeutics: Molecular Therapeutics
Meeting:
2008 ASCO Annual Meeting

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E-Mail Article

Abstract No:
3594
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 3594)
Author(s):
M. Scaltriti, C. Verma, M. Guzman, J. Jimenez, J. Parra, K. Pedersen, S. Landolfi, S. Ramon y Cajal, J. Arribas, J. Baselga
Abstract:
Background: Lapatinib is a HER2 tyrosine kinase inhibitor that has clinical activity in HER2 overexpressing (HER2+) breast cancer. In vitro and clinical studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. In order to dissect the differential mechanims of these agents, we have studied the effects of lapatinib and trastuzumab on receptor expression and signaling and have explored a new potential mechanism underlying the profound antitumor activity of the combination. Methods: HER2+ breast cancer cells SKBR3 and MCF7-HER2 were treated with lapatinib, trastuzumab or both. Assays of receptor expression, phosphorylation, signalling and tumor growth were performed. Trastuzumab-dependent cellular cytotoxicity was measured with different levels of HER2 expression and doses of lapatinib. Results: Lapatinib treatment of HER2+ breast cancer cells inhibited HER2 phosphorylation, prevented ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modelling techniques we further demonstrated that the lapatinib-induced accumulation of HER2 lead to stabilization of inactive HER2 homo- and hetero-dimers. Accumulation of HER2 induced by lapatinib and downregulation of HER2 mediated by trastuzumab were also observed in vivo, where the combination of the two agents triggered complete tumor remission in all cases after 10 days of treatment. Lapatinib-induced accumulation of HER2 at the cell surface markedly enhanced trastuzumab-mediated ADCC. Conclusions: Lapatinib results in a marked accumulation of inactive HER2 receptors at the cell surface both in vitro and in vivo. This increase in receptors number at the cell surface enhances ADCC by trastuzumab. We propose that this is a novel mechanism that may be clinically relevant and exploitable in the therapy of patients with HER2+ tumors

Best of luck and Let us know how you do!

08-03-2008, 06:08 AM	#3
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	Esther there was a wonderful poster at ASCO on the tykerb herceptin combination I was told the article is to come out soon in ONCOGENE Home > Abstracts & Virtual Meeting > Abstracts > 2008 ASCO Annual Meeting Effect of lapatinib on accumulation of inactive HER2 at the cell membrane and on antibody-dependent cellular cytotoxicity (ADCC) mediated by trastuzumab: A novel mechanism for the enhanced effects of combined anti-HER2 therapy. Sub-category: Tyrosine Kinase Inhibitors Category: Developmental Therapeutics: Molecular Therapeutics Meeting: 2008 ASCO Annual Meeting Printer Friendly E-Mail Article Abstract No: 3594 Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 3594) Author(s): M. Scaltriti, C. Verma, M. Guzman, J. Jimenez, J. Parra, K. Pedersen, S. Landolfi, S. Ramon y Cajal, J. Arribas, J. Baselga Abstract: Background: Lapatinib is a HER2 tyrosine kinase inhibitor that has clinical activity in HER2 overexpressing (HER2+) breast cancer. In vitro and clinical studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. In order to dissect the differential mechanims of these agents, we have studied the effects of lapatinib and trastuzumab on receptor expression and signaling and have explored a new potential mechanism underlying the profound antitumor activity of the combination. Methods: HER2+ breast cancer cells SKBR3 and MCF7-HER2 were treated with lapatinib, trastuzumab or both. Assays of receptor expression, phosphorylation, signalling and tumor growth were performed. Trastuzumab-dependent cellular cytotoxicity was measured with different levels of HER2 expression and doses of lapatinib. Results: Lapatinib treatment of HER2+ breast cancer cells inhibited HER2 phosphorylation, prevented ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modelling techniques we further demonstrated that the lapatinib-induced accumulation of HER2 lead to stabilization of inactive HER2 homo- and hetero-dimers. Accumulation of HER2 induced by lapatinib and downregulation of HER2 mediated by trastuzumab were also observed in vivo, where the combination of the two agents triggered complete tumor remission in all cases after 10 days of treatment. Lapatinib-induced accumulation of HER2 at the cell surface markedly enhanced trastuzumab-mediated ADCC. Conclusions: Lapatinib results in a marked accumulation of inactive HER2 receptors at the cell surface both in vitro and in vivo. This increase in receptors number at the cell surface enhances ADCC by trastuzumab. We propose that this is a novel mechanism that may be clinically relevant and exploitable in the therapy of patients with HER2+ tumors Best of luck and Let us know how you do!