Key result
GW2974, but not trastuzumab, activates AMP-activated protein kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNFalpha-induced cell death.
GW2974 protects cardiomyocytes from TNFalpha-induced cell death by activating AMPK, suggesting a potential strategy to mitigate cardiotoxicity from chemotherapy or ischemia.
Answers are grounded in this paper and cite their sources.
Differential AMPK activation by HER2 inhibitors may explain variable cardiotoxicity; leaves open mechanistic targets for prevention in trastuzumab-treated patients.
The human EGF receptor (HER) 2 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 (Genentech, South San Francisco, CA), particularly in patients with prior exposure to cardiotoxic chemotherapies e.g., anthracyclines. Here, we show that GW2974 (HER2/EGF receptor tyrosine kinase inhibitor), but not trastuzumab, activates AMP-activated protein kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNFalpha-induced cell death. GW2974 stimulates calcium dependent fatty acid oxidation in vitro and in the 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.
No takes yet. Share an insight, caveat, or question.
Spector et al. (2007) studied Cardiomyopathy associated with anti-HER2 therapy. GW2974 vs. Trastuzumab was evaluated on AMPK activation and protection against TNFalpha-induced cell death. GW2974, but not trastuzumab, activates AMP-activated protein kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNFalpha-induced cell death.
Synapse has enriched 10 related papers. Consider them for comparative context: