Journal
CANCER BIOLOGY & THERAPY
Volume 11, Issue 9, Pages 793-800Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.11.9.15045
Keywords
HER2 (ERBB2); trastuzumab; lapatinib; drug resistance; antibodies; tyrosine kinase inhibitors
Categories
Funding
- ACS [CRP-07-234, 118813-PF-10-070-01-TBG]
- Lee Jeans Translational Breast Cancer Research Program
- Breast Cancer Specialized Program of Research Excellence (SPORE) [P50 CA98131]
- Vanderbilt-Ingram Cancer Center [P30 CA68485]
- DOD [BC093376]
- [R01]
- [CA80195]
- [T32DK007563]
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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.
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