KDM6B Counteracts EZH2-Mediated Suppression of to Confer Resistance to PI3K/AKT Inhibitor Treatment in Breast Cancer.

Despite showing promise against -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 expression provides a protective mechanism for PI3K/AKT inhibitor-induced apoptosis in breast cancer cells. We found that overexpression of and in luminal breast cancer are positively associated with poorer disease outcomes. Mechanistically, KDM6B promotes expression by antagonizing EZH2-mediated repression, and pharmacologic inhibition of KDM6B augments apoptotic response to PI3K/AKT inhibitor treatment. Moreover, the 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 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. .