Data from BMS-536924 Reverses IGF-IR-Induced Transformation of Mammary Epithelial Cells and Causes Growth Inhibition and Polarization of MCF7 Cells

Abstract

<div>Abstract<p><b>Purpose:</b> This study aimed to test the ability of a new insulin-like growth factor receptor (<i>IGF-IR</i>) tyrosine kinase inhibitor, BMS-536924, to reverse the ability of constitutively active <i>IGF-IR</i> (<i>CD8-IGF-IR</i>) to transform MCF10A cells, and to examine the effect of the inhibitor on a range of human breast cancer cell lines.</p><p><b>Experimental Design:</b><i>CD8-IGF-IR</i>-MCF10A cells were grown in monolayer culture, three-dimensional (3D) culture, and as xenografts, and treated with BMS-536924. Proliferation, cell cycle, polarity, and apoptosis were measured. Twenty-three human breast cancer cell lines were treated in monolayer culture with BMS-536924, and cell viability was measured. MCF7, MDA-MB-231, and MDA-MB-435 were treated with BMS-536924 in monolayer and 3D culture, and proliferation, migration, polarity, and apoptosis were measured.</p><p><b>Results:</b> Treatment of <i>CD8-IGF-IR</i>-MCF10A cells grown in 3D culture with BMS-536924 caused a blockade of proliferation, restoration of apical-basal polarity, and enhanced apoptosis, resulting in a partial phenotypic reversion to normal acini. In monolayer culture, BMS-536924 induced a dose-dependent inhibition of proliferation, with an accumulation of cells in G<sub>0</sub>/G<sub>1,</sub>, and completely blocked <i>CD8-IGF-IR</i>–induced migration, invasion, and anchorage-independent growth. <i>CD8-IGF-IR</i>-MCF10A xenografts treated with BMS-536924 (100 mg/kg/day) showed a 76% reduction in xenograft volume. In a series of 23 human breast cancer cell lines, BMS-536924 inhibited monolayer proliferation of 16 cell lines. Most strikingly, treatment of MCF7 cells grown in 3D culture with BMS-536924 caused blockade of proliferation, and resulted in the formation of hollow polarized lumen.</p><p><b>Conclusions:</b> These results show that the new small molecule BMS-536924 is an effective inhibitor of <i>IGF-IR</i>, causing a reversion of an <i>IGF-IR</i>–mediated transformed phenotype.</p></div>