Data from KDM6B Counteracts EZH2-Mediated Suppression of <i>IGFBP5</i> to Confer Resistance to PI3K/AKT Inhibitor Treatment in Breast Cancer

Abstract

<div>Abstract<p>Despite showing promise against <i>PIK3CA</i>-mutant breast cancers in preclinical studies, PI3K/AKT pathway inhibitors demonstrate limited clinical efficacy as monotherapy. Here, we found that histone H3K27me3 demethylase KDM6B-targeted <i>IGFBP5</i> expression provides a protective mechanism for PI3K/AKT inhibitor-induced apoptosis in breast cancer cells. We found that overexpression of <i>KDM6B</i> and <i>IGFBP5</i> in luminal breast cancer are positively associated with poorer disease outcomes. Mechanistically, KDM6B promotes <i>IGFBP5</i> expression by antagonizing EZH2-mediated repression, and pharmacologic inhibition of KDM6B augments apoptotic response to PI3K/AKT inhibitor treatment. Moreover, the <i>IGFBP5</i> expression is upregulated upon acquired resistance to the PI3K inhibitor GDC-0941, which is associated with an epigenetic switch from H3K27me3 to H3K27Ac at the <i>IGFBP5</i> gene promoter. Intriguingly, GDC-0941–resistant breast cancer cells remained sensitive to KDM6B or IGFBP5 inhibition, indicating the dependency on the KDM6B–IGFBP5 axis to confer the survival advantage in GDC-0941–resistant cells. Our study reveals an epigenetic mechanism associated with resistance to targeted therapy and demonstrates that therapeutic targeting of KDM6B-mediated IGFBP5 expression may provide a useful approach to mitigate both intrinsic and acquired resistance to the PI3K inhibitor in breast cancer. <i>Mol Cancer Ther; 17(9); 1973–83. ©2018 AACR</i>.</p></div>