Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer.
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Targeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking. To address this critical question, we undertook a concerted approach using patient expression data sets, HER2-positive cell lines, and tumor samples biopsied both before and after trastuzumab treatment. Together, these methods revealed that high expression and activation of a specific subset of receptor tyrosine kinases (RTKs) was strongly associated with poor clinical prognosis and the development of resistance. Mechanistically, these RTKs are capable of maintaining downstream signal transduction to promote tumor growth via the suppression of cellular senescence. Consequently, these findings provide the rationale for the design of therapeutic strategies for overcoming drug resistance in breast cancer via combinational inhibition of the limited number of targets from this specific subset of RTKs.
human epidermal growth factor receptor 2 (HER2)
insulin-like growth factor (IGF)
receptor tyrosine kinase
Cell Line, Tumor
Drug Resistance, Neoplasm
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Published Version (Please cite this version)10.1074/jbc.M116.754960
Publication InfoAlexander, Peter B; Chen, Rui; Gong, Chang; Yuan, Lifeng; Jasper, Jeff S; Ding, Yi; ... Wang, Xiao-Fan (2017). Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer. J Biol Chem, 292(2). pp. 748-759. 10.1074/jbc.M116.754960. Retrieved from https://hdl.handle.net/10161/15359.
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Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology, in the School of Medicine
The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Specifically we are interested in the pharmaceutical exploitation of the estrogen and androgen receptors as therapeutic targets in breast and prostate cancers and in defining how these receptors influence the pathogenesis of these diseases. These efforts have led to the discovery of severa
Donald and Elizabeth Cooke Distinguished Professor of Cancer Research, in the School of Medicine
The current research in the Wang laboratory mainly focuses on the elucidation of molecular nature and signaling mechanisms associated with the initiation of cellular senescence. In addition, we continue to study changes in tumor microenvironment that promotes tumor progression and metastasis, particularly how tumor cells interact with the immune system. Ultimately, we hope that our studies in these areas to lead to the development of novel therapeutics for the treatment of various types of human
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