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

Joan T. Garrett, Carlos L. Arteaga

Research output: Contribution to journalReview articlepeer-review

111 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)793-800
Number of pages8
JournalCancer Biology and Therapy
Issue number9
StatePublished - May 1 2011


  • Antibodies
  • Drug resistance
  • HER2 (ERBB2)
  • Lapatinib
  • Trastuzumab
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research


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