Lapatinib and 17AAG Reduce <sup>89</sup>Zr-Trastuzumab-F(ab′)<sub>2</sub> Uptake in SKBR3
Tumor Xenografts
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Abstract
Human epidermal growth factor receptor-2 (HER2) directed
therapy
potentially can be improved by insight in drug effects on HER2 expression.
This study evaluates the effects of the EGFR/HER2 tyrosine kinase
inhibitor lapatinib, the heat shock protein-90 inhibitor 17AAG, and
their combination, on HER2 expression with <i>in vivo</i> HER2-PET imaging. Lapatinib and 17AAG effects on EGFR and HER2 membrane
expression were determined <i>in vitro</i> using flow cytometry
of human SKBR3 tumor cells. Effect of lapatinib on HER2 internalization
was studied <i>in vitro</i> by <sup>89</sup>Zr-trastuzumab-F(ab′)<sub>2</sub> internalization. For <i>in vivo</i> evaluation, <sup>89</sup>Zr-trastuzumab-F(ab′)<sub>2</sub> μPET imaging
was performed two times with a 7 day interval. Lapatinib was administered
for 6 days, starting 1 day after the baseline scan. 17AAG was given
1 day before the second <sup>89</sup>Zr-trastuzumab-F(ab′)<sub>2</sub> injection. Imaging data were compared with <i>ex vivo</i> biodistribution analysis and HER2 immunohistochemical staining.
17AAG treatment lowered EGFR expression by 41% (<i>P</i> = 0.016) and HER2 by 76% (<i>P</i> = 0.022). EGFR/HER2
downregulation by 17AAG was inhibited by lapatinib pretreatment. Lapatinib
reduced internalization of <sup>89</sup>Zr-trastuzumab-F(ab′)<sub>2</sub> with 25% (<i>P</i> = 0.0022). <sup>89</sup>Zr-trastuzumab-F(ab′)<sub>2</sub> tumor to blood ratio was lowered 32% by lapatinib (<i>P</i> = 0.00004), 34% by 17AAG (<i>P</i> = 0.0022)
and even 53% by the combination (<i>P</i> = 0.011). Lapatinib
inhibits HER2 internalization and 17AAG lowers HER2 membrane expression.
Both drugs reduce <sup>89</sup>Zr-trastuzumab-F(ab′)<sub>2</sub> tumor uptake. Based on our findings, supported by previous preclinical
data indicating the antitumor potency of lapatinib in combination
with HSP90 inhibition, combination of these drugs deserves further
investigation