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PMID: 21307659 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review

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

Cancer biology & therapy ·Vol. 11 ·No. 9 ·2011-05-01 ·Pages 793-800

Garrett JT, Arteaga CL

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.

MeSH Terms
Antibodies, Monoclonal/pharmacology Antineoplastic Agents/pharmacology Drug Resistance, Neoplasm Humans Protein Kinase Inhibitors/pharmacology,therapeutic use Protein-Tyrosine Kinases/antagonists & inhibitors Receptor, ErbB-2/antagonists & inhibitors
Chemicals
Antibodies, Monoclonal Antineoplastic Agents Protein Kinase Inhibitors Protein-Tyrosine Kinases Receptor, ErbB-2
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Garrett Joan T
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Arteaga Carlos L
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Article Info
Journal
Cancer biology & therapy
Abbr.
Cancer Biol Ther
ISSN
1555-8576
DOI
10.4161/cbt.11.9.15045
Published
2011-05-01
Epub
2011-00-01
Pages
793-800
Language
English
Region
United States
NLM ID
101137842
PMCID
PMC3230295
Subset
IM
Grants
NCI NIH HHS · R01 CA080195 · United States
NCI NIH HHS · P50 CA98131 · United States
NCI NIH HHS · P30 CA68485 · United States
NCI NIH HHS · R01 CA80195 · United States
NCI NIH HHS · P50 CA098131 · United States
NCI NIH HHS · P30 CA068485 · United States
NIDDK NIH HHS · T32 DK007563 · United States
NIDDK NIH HHS · T32DK007563 · United States
External Links
PubMed source DOI: 10.4161/cbt.11.9.15045 PMC Full Text View journal details
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