Lapatinib, a dual HER1/HER2 tyrosine kinase inhibitor, augments basal cleavage of HER2 extracellular domain (ECD) to inhibit HER2-driven cancer cell growth

Journal of Cellular Physiology
Alejandro Vázquez-MartínJavier A Menendez

Abstract

The ultimate biological and clinical meaning of shed HER2 extracellular domain (ECD) has remained largely unclear until recently. Oversecretion of soluble HER2 ECD has been shown to inhibit growth of HER2-overexpressing cancer cells by promoting HER2 ECD dimerization with HER transmembrane receptors thus impairing their cross-tyrosine phosphorylation and decreasing their activation status. HER2-targeted drugs capable to enhance the occurrence of basal HER2 ECD shedding but simultaneously preventing formation of truncated cell membrane-bound HER2 intracellular fragment, which exhibits an undesirable constitutive kinase activity, might be extremely efficient at managing HER2-positive cancer disease. The dual HER1/HER2 Tyrosine Kinase inhibitor lapatinib, which works intracellularly and directly targets the TK domain of HER2, drastically augments basal shedding of HER2 ECD to inhibit HER2-driven cancer cell growth. Lapatinib treatment significantly augments the concentration of the inactive (unphosphorylated) form of HER2 protein at the tumor cell membrane and promotes an exacerbated HER2 ECD shedding to the extracellular milieu of HER2-overexpressing cancer cells. Exacerbated sensitivity of trastuzumab-resistant cancer cells, whi...Continue Reading

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Citations

Jan 22, 2013·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Xiaohong DengAnne-Sofie Schrohl
Nov 18, 2010·Breast Cancer Research : BCR·Quanri JinFrancisco J Esteva
Apr 24, 2012·Biochimica Et Biophysica Acta·Lian LamHongtao Zhang
May 10, 2011·Cancer Treatment Reviews·Chantal TséPierre-Jean Lamy
Oct 22, 2016·Endocrine-related Cancer·Patricia V ElizaldeRoxana Schillaci
Oct 28, 2016·Journal of Neurochemistry·Hannah SchneiderMichael Weller
Aug 8, 2014·Membranes·Vibeke Bertelsen, Espen Stang
Oct 31, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Denis M CollinsJohn Crown
Sep 26, 2012·Molecular Pharmaceutics·Thijs H Oude MunninkMarjolijn N Lub-de Hooge

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