New insight into lapatinib
The increase of HER2 dimer formation that results from inhibition of ubiquitination by laptinib actually allows greater trastuzumab-mediated cytolysis and this synergism should be further explored in clinical trials
Women with breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) experience more malignant disease and a poorer prognosis; HER-2 overexpression is found in a large proportion (25–30%) of human breast tumors. Lapatinib, an inhibitor of HER2 tyrosine kinase, has shown clinical benefit in these cancers, as has trastuzumab, a humanized monoclonal antibody that binds the extracellular domain of HER2. The exact mechanism for trastuzumab activity remains but hypotheses include down regulation of the receptor, cell cycle arrest, angiogenesis inhibition and the induction of antibody-dependent cell-mediated cytotoxicity.
Although some HER-2 positive tumors benefit from treatment with either agent, many remain resistant to lapatinib and trastuzumab when administered alone, leading researchers to explore their dual administration. A recent phase III trial demonstrated improved clinical outcome in patients when lapatinib and trastuzumab are administered together over lapatinib alone.
In the May, 2009 issue of Nature Reviews Clinical Oncology Aujla comments an article published by Scaltriti et al. in the Oncogene on attempt to elucidate the mechanisms of action and explain how these two agents may work together to achieve a stronger effect. They found that lapatinib treatment increased HER2 levels at the cell surface and that it had a higher affinity, even higher than ATP, for HER2 monomers than for EGFR monomers, which resulted in higher stability of HER2 dimers. Next, they investigated the degree of receptor ubiquitination and found that cells treated with lapatinib, either alone or with trastuzumab, had barely discernable levels of ubiquinated receptor. The turnover rate of HER2 in cells treated with either agent alone or in combination was determined in time-course experiments. In lapatinib treated cells, either singly or in conjunction with trastuzumab, HER2 was stable at high levels for up to 48 hours, compared with controls. Trastuzumab treated cells showed an increase in HER2 ubiquitination, subsequent degradation, and turnover.
In parallel experiments in BT474 xenograft mice, both lapatinib and trastuzumab caused tumor regression; mice treated with both agents achieved complete tumor regression within 10 days of treatment. Upon tumor analysis, HER2 expression was increased in animals treated with lapatinib alone but decreased with trastuzumab treatment. HER2 induction by lapatinib was associated with heightened trastuzumab-dependent cell cytotoxicity, thus providing a possible mechanism for the benefit seen in HER2 positive tumors treated with both agents.
The increase of HER2 dimer formation that results from inhibition of ubiquitination by laptinib actually allows greater trastuzumab-mediated cytolysis and this synergism should be further explored in clinical trials.
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