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Cancer Biol Ther. 2011 May 1;11(9):793-800. Epub 2011 May 1.

Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: mechanisms and clinical implications.

Author information

1
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.

Abstract

The antibody trastuzumab and the tyrosine kinase inhibitor lapatinib are approved by the FDA for the treatment of HER2-overexpressing breast cancer. These anti-HER2 drugs are changing the natural history of HER2-overexpressing breast cancer. However, therapeutic resistance to trastuzumab or lapatinib, as either single-agents or in combination with chemotherapy in the metastatic setting, typically occurs within months of starting therapy. Several mechanisms of trastuzumab-resistance have been reported that include signaling from other HER receptors, signaling from receptor tyrosine kinases (RTKs) outside of the HER (ErbB) family, increased phosphatidylinositol 3-kinase signaling, and the presence of truncated forms of HER2. Mechanisms of resistance to lapatinib also point to increased phosphatidylinositol 3-kinase signaling as well as derepression/activation of compensatory survival pathways. In this review, we discuss how these models and mechanisms enhance our understanding of the clinical resistance to HER2-directed therapies.

PMID:
21307659
PMCID:
PMC3230295
DOI:
10.4161/cbt.11.9.15045
[Indexed for MEDLINE]
Free PMC Article

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