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RobinP · 06-04-2006, 12:03 PM

Patty I am posting this article as well which further discusses the use of anti-estrogens with erb targeted therapies. Hope it helps...

Mechanism of action associated with response to erbB targeted therapy.

2005 ASCO Annual Meeting

Abstract No:

676

Citation:

Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 676

Author(s):

S. S. Bacus, J. Hill, G. Hortobagyi, N. Spector

Abstract:

Background: ErbB receptors are associated with aggressive cancers and are therapeutic targets for drugs, such as antibodies or small molecules that block receptor kinase activity and downstream signaling pathways. Nuclear cellular receptors, such estrogen receptor (ER) and progesterone receptor (PR), are also targeted for anti-hormone therapies. There is an inverse correlation between ErbB2 receptor expression and ER and PR. In patients with increased expression levels of ErbB2 anti-hormone therapies are less effective. In addition, the estrogen receptors pathway upregulates the anti-apoptotic factor Bcl2 which is associated with resistance to various therapies. Methods: Breast cancer biopsies from patients treated with small molecule inhibitors to erbB receptors or antibodies were analyzed for ER, PR, Bcl2 and ErbB receptors. In addition, the breast cancer cell line Au-565, that overexpresses ErbB2, was transfected with either ER or Bcl2 cDNAs. The cells were treated with Herceptin or a dual EGFR/ErbB2 inhibitor GW2974 (Lapatinib). Cells were analyzed by Western Blot analysis. Breast biopsies from patients before and after treatment were tested for the expression of various markers such as EGFR, ErbB2, IGF-1R, TGFα, Bcl-2, ER, PR, cyclin D1 and phosphorylated Erk, Akt and S6 ribosomal protein by immunohistochemistry (IHC). Results: Patients treated with the erbB inhibitors that expressed ER, PR and Bcl2 were resistant to treatments. Cells that expressed ER, PR and Bcl2 were resistant to ErbB targeted therapies. The addition of anti-hormone therapies overcame this resistance. Estrogen upregulated Bcl2 and downregulated ErbB receptors. Inhibition of ErbB receptors upregulated the estrogen and progesterone pathway and Bcl2. Conclusions: The nuclear hormone receptor pathway and the ErbB oncogenic receptor pathway interacts with each other to affect the response to ErbB targeted therapies. Strategies combining the selectivity of inhibitors to ErbB receptors together with anti-hormone therapies, hold promise in treating breast cancers.

06-04-2006, 12:03 PM	#13
RobinP Senior Member Join Date: Nov 2005 Posts: 943	More on antiestrogen therapy with erb target therapies... Patty I am posting this article as well which further discusses the use of anti-estrogens with erb targeted therapies. Hope it helps... Mechanism of action associated with response to erbB targeted therapy. 2005 ASCO Annual Meeting Abstract No: 676 Citation: Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 676 Author(s): S. S. Bacus, J. Hill, G. Hortobagyi, N. Spector Abstract: Background: ErbB receptors are associated with aggressive cancers and are therapeutic targets for drugs, such as antibodies or small molecules that block receptor kinase activity and downstream signaling pathways. Nuclear cellular receptors, such estrogen receptor (ER) and progesterone receptor (PR), are also targeted for anti-hormone therapies. There is an inverse correlation between ErbB2 receptor expression and ER and PR. In patients with increased expression levels of ErbB2 anti-hormone therapies are less effective. In addition, the estrogen receptors pathway upregulates the anti-apoptotic factor Bcl2 which is associated with resistance to various therapies. Methods: Breast cancer biopsies from patients treated with small molecule inhibitors to erbB receptors or antibodies were analyzed for ER, PR, Bcl2 and ErbB receptors. In addition, the breast cancer cell line Au-565, that overexpresses ErbB2, was transfected with either ER or Bcl2 cDNAs. The cells were treated with Herceptin or a dual EGFR/ErbB2 inhibitor GW2974 (Lapatinib). Cells were analyzed by Western Blot analysis. Breast biopsies from patients before and after treatment were tested for the expression of various markers such as EGFR, ErbB2, IGF-1R, TGFα, Bcl-2, ER, PR, cyclin D1 and phosphorylated Erk, Akt and S6 ribosomal protein by immunohistochemistry (IHC). Results: Patients treated with the erbB inhibitors that expressed ER, PR and Bcl2 were resistant to treatments. Cells that expressed ER, PR and Bcl2 were resistant to ErbB targeted therapies. The addition of anti-hormone therapies overcame this resistance. Estrogen upregulated Bcl2 and downregulated ErbB receptors. Inhibition of ErbB receptors upregulated the estrogen and progesterone pathway and Bcl2. Conclusions: The nuclear hormone receptor pathway and the ErbB oncogenic receptor pathway interacts with each other to affect the response to ErbB targeted therapies. Strategies combining the selectivity of inhibitors to ErbB receptors together with anti-hormone therapies, hold promise in treating breast cancers. __________________ Robin 2002- dx her2 positive DCIS/bc TX Mast, herceptin chemo Last edited by RobinP; 06-04-2006 at 12:11 PM..