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Speaker: Sarah S. Bacus, PhD
President and Chief Scientific Officer
Targeted Molecular Diagnostics, LLC
Westmont, Illinois
website: http://www.tmdlab.com
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Topic:
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"Activation of the AMP Kinase Regulated Metabolic Stress Response
By a Small Molecule HER2/EGFR Kills Cancer Cells
But Protects Cardiac Myocytes From Apoptotic Stimuli" |
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The HER2 receptor tyrosine kinase is a survival factor for human cardiomyocytes, and its inhibition may explain the increased incidence of cardiomyopathy associated with the anti-HER2 monoclonal antibody (trastuzumab/Herceptin), particularly in patients with prior exposure to cardiotoxic chemotherapies e.g., anthracyclines. Here we show that GW2974, a HER2/EGFR tyrosine kinase inhibitor, but not trastuzumab, activates AMP-activated protein kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNF -induced cell death. GW2974 (Lapatinib/Tykerb) stimulates calcium dependent fatty acid oxidation in vitro and in myocardium of GW2974-treated rodents. Calcium chelation or siRNA-targeted AMPK knockdown blocks GW2974 induced fatty acid oxidation. In addition, inhibition of AMPK by a specific inhibitor resulted in increased killing of cardiomyocytes. Elucidating the effects of HER2-targeted therapies on AMPK may predict for risk of cardiomyopathy, and provide a novel HER2-targeted strategy designed to protect myocardium from the pro-apoptotic effects of pro-inflammatory cytokines released in response to cardiac injury by chemotherapy or acute ischemia.
We propose that cancer cell killing by targeted therapy based on inhibition of tyrosine kinase may depend on metabolic changes from high glycolysis (Warburg effect) in cancers cells to energy production by TCA. Thus, the very mechanism that protects HMC from TNFa induced killing, may contribute to the mechanism of anti-tumor activity by GW2974 and related compounds. In light of the protect6ive effect of GW2974, selective HER2 kinase inhibitors that activate AMPK might provide a novel targeted approach to protect myocardium from apoptosis induced by proinflammatory cytokines
released in response to active ischemia injury, warranting further investigation. |
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When:
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Monday, February 12, 2007
12:00PM – 1:00PM
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Location:
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Baldwin Auditorium
Robert H. Lurie Medical Research Center
303 East Superior Street, 1st floor
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Selected Recent References for Sarah S. Bacus, PhD
Xia W, Husain I, Liu L, Bacus S, Saini S, Spohn J, Pry K, Westlund R, Stein SH, Spector NL. Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers. Cancer Res. 2007 Feb 1;67(3):1170-5.
Xia W, Bacus S, Hegde P, Husain I, Strum J, Liu L, Paulazzo G, Lyass L, Trusk P, Hill J, Harris J, Spector NL. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7795-800. Epub 2006 May 8.
Xia W, Bisi J, Strum J, Liu L, Carrick K, Graham KM, Treece AL, Hardwicke MA, Dush M, Liao Q, Westlund RE, Zhao S, Bacus S, Spector NL. Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res. 2006 Feb 1;66(3):1640-7.
Bacus SS, Gudkov AV, Esteva FJ, Yarden Y. Expression of erbB receptors and their ligands in breast cancer: implications to biological behavior and therapeutic response. Breast Dis. 2000;11:63-75.
Friedman LM, Rinon A, Schechter B, Lyass L, Lavi S, Bacus SS, Sela M, Yarden Y. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1915-20. Epub 2005 Jan 31.
Kochupurakkal BS, Harari D, Di-Segni A, Maik-Rachline G, Lyass L, Gur G, Kerber G, Citri A, Lavi S, Eilam R, Chalifa-Caspi V, Eshhar Z, Pikarsky E, Pinkas-Kramarski R, Bacus SS, Yarden Y. Epigen, the last ligand of ErbB receptors, reveals intricate relationships between affinity and mitogenicity. J Biol Chem. 2005 Mar 4;280(9):8503-12. Epub 2004 Dec 17.
 View more Publications by Sarah S. Bacus, PhD
listed in the National Library of Medicine (PubMed) |
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