PI3K/mTOR Inhibition Markedly Potentiates HDAC Inhibitor Activity in NHL Cells through BIM- and MCL-1–Dependent Mechanisms <i>In Vitro</i> and <i>In Vivo</i>

Abstract

BEZ235/panobinostat exhibits potent anti-DLBCL activity, including in poor-prognosis ABC- and double-hit subtypes, but not in normal CD34(+) cells. Synergism is most likely multifactorial, involving AKT inactivation/GSK3 activation, Bim upregulation, Mcl-1 downregulation, enhanced DNA damage, and is operative in vivo. Combined PI3K/mTOR and HDAC inhibition warrants further attention in DLBCL.