Modeling the consequences of epidermal growth factor receptor inhibition on cardiac development, function, and homeostasis Public Deposited
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- Last Modified
- March 21, 2019
Barrick, Cordelia Johnson
- Affiliation: School of Medicine, Curriculum in Toxicology
- The epidermal growth factor receptor (EGFR/ERBB1) is the prototypical and first discovered member of the ERBB family of receptor tyrosine kinases. As transmembrane receptors, their primary function is to translate extracellular signals into cellular response. Signaling is initiated through binding by members of the EGF ligand family, which induces receptor homodimerization or heterodimerization with other ERBB receptors (ERBB2, ERBB3 or ERBB4). Activation of downstream cytoplasmic signaling pathways occurs, leading to alterations in biological responses such as cellular proliferation, survival, motility, and adhesion. As EGFR is expressed in most developing and adult tissues, misregulation or dysfunction of EGFR activity severely impacts embryonic viability, tissue maintenance and multiple disease processes. Since EGFR was first proposed as a cancer drug target over twenty years ago, substantial research has defined a central role for aberrant ERBB signaling in cancer and led to the design of targeted therapies that effectively inhibit receptor activity. However, significant cardiotoxicity was observed in clinical trials targeting the closely related ERBB2 receptor, necessitating further studies on the role of ERBB signaling in cardiac development and function. Genetic ablation of any of the ERBB receptors, select ligands, or ligand-processing enzymes results in severe congenital cardiac defects, often causing embryonic lethality. Direct stimulation of ERBB2/ERBB4 heterodimers by the ligand neuregulin-1 (NRG1) supports cardiomyocyte survival, while GPCR mediated transactivation of EGFR likely plays a significant role in cardiac hypertrophy and hypertension. These discoveries have fostered interest in novel therapies targeting the EGFR signaling pathway for the treatment of several common cardiovascular diseases. However, the effects of chronic EGFR inhibition on cardiovascular homeostasis have not been evaluated. Through the use of mouse models, we demonstrated that genetic or pharmaceutical repression of EGFR signaling significantly altered cardiac function and homeostasis. Since the cardiac phenotype of mice harboring a hypomorphic mutation in Egfr was strongly dependent on genetic background, we broadly localized quantitative trait loci (QTL) which modulate the cardiac phenotype. These studies should be useful in predicting degenerative cardiac changes associated with EGFR inhibition which may be overlooked in short term clinical trials, and may advance understanding of the role of EGFR in cardiac development and function.
- Date of publication
- August 2007
- Resource type
- Rights statement
- In Copyright
- Threadgill, David W.
- Degree granting institution
- University of North Carolina at Chapel Hill
- Open access
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|Modeling the consequences of epidermal growth factor receptor inhibition on cardiac development, function, and homeostasis||2019-04-11||Public||