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Differential action of small molecule HER kinase inhibitors on receptor heterodimerization: Therapeutic implications
Author(s) -
SánchezMartín M.,
Pandiella A.
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26358
Subject(s) - lapatinib , tyrosine kinase , mechanism of action , receptor , neratinib , cancer research , receptor tyrosine kinase , microbiology and biotechnology , kinase , biology , tropomyosin receptor kinase c , pharmacology , chemistry , biochemistry , trastuzumab , cancer , platelet derived growth factor receptor , in vitro , breast cancer , genetics , growth factor
Deregulation of ErbB/HER receptor tyrosine kinases has been linked to several types of cancer. The mechanism of activation of these receptors includes establishment of receptor dimers. Here, we have analyzed the action of different small molecule HER tyrosine kinase inhibitors (TKIs) on HER receptor dimerization. Breast cancer cell lines were treated with distinct TKIs and the formation of HER2‐HER3 dimers was analyzed by coimmunoprecipitation and western blot or by Förster resonance energy transfer assays. Antibody‐dependent cellular cytotoxicity was analyzed by measuring the release of lactate dehydrogenase and cell viability. Lapatinib and neratinib interfered with ligand‐induced dimerization of HER receptors; while pelitinib, gefitinib, canertinib or erlotinib did not. Moreover, lapatinib and neratinib were able to disrupt previously formed receptor dimers. Structural analyses allowed the elucidation of the mechanism by which some TKIs prevent the formation of HER receptor dimers, while others do not. Experiments aimed at defining the functional importance of dimerization indicated that TKIs that impeded dimerization prevented down‐regulation of HER2 receptors, and favored the action of trastuzumab. We postulate that TKIs that prevent dimerization and down‐regulation of HER2 may augment the antitumoral action of trastuzumab, and this mechanism of action should be considered in the treatment of HER2 positive tumors which combine TKIs with antireceptor antibodies.