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Interrupting Growth Signaling in HER2-overexpressing Tumors
Genentech BioOncology is a pioneer in the discovery and description of key HER signaling mechanisms. In 1987, Genentech BioOncology scientists and their colleagues confirmed the importance of cellular growth signaling via the HER2 receptor. In addition, overexpression of the HER2 receptor has been found to correlate with more aggressive forms of cancer.55
HER2 Signaling MOA animation
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HER cellular signaling is initiated when two receptor molecules join together in a process called dimerization, which occurs in response to the presence of a growth factor molecule (ligand).50
There are four known HER proteins: HER1, 2, 3, and 4. HER2 is able to dimerize with itself (homodimerization), and while there is no known ligand for HER2, this receptor plays a pivotal role in HER-mediated signaling as the preferred partner for dimerization with HER1, 3, and 4 (heterodimerization), the most potent combination of which appears to be the HER2/HER3 dimer.50
Dimerization of different members of this family, including HER1, HER2, HER3, and HER4, may lead to activation of different kinase-mediated intracellular signaling cascades, including the PI3K and MAPK pathways, although to date, no HER3-associated kinase activity has been identified.48,50,51
Inappropriate signaling can occur as a result of overexpression of receptor proteins or when receptors are expressed at normal levels but are inappropriately activated. HER overexpression and/or dysregulation may lead to increased/uncontrolled proliferation, decreased apoptosis (programmed cell death), enhanced tumor cell motility, and angiogenesis.48,49,52
Genentech BioOncology continues to investigate HER2 and other components of the HER pathway and how the various components interact with each other. It is these interactions, or "cross talk," that may provide multiple approaches to interfering with these signals and inhibiting cancer through this pathway.
Journal Articles
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Prenzel N, Fischer OM, Streit S, et al. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer. 2001;8:11-31.
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Linggi B, Carpenter G. ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol. 2006;16:649-656.
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Sundaresan S, Penuel E, Sliwkowski MX. The biology of human epidermal growth factor receptor 2. Curr Oncol Rep. 1999;1:16-22.
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Spivak-Kroizman T, Rotin D, Pinchasi D, et al. Heterodimerization of c-erbB2 with different epidermal growth factor receptor mutants elicits stimulatory or inhibitory responses. J Biol Chem. 1992;267:8056-8063.
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Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta. 1994;1198:165-184.
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Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.
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