Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2

摘要: The mammalian target of rapamycin (mTOR) has emerged as an important therapeutic for diffuse large B-cell lymphoma (DLBCL), recent studies have demonstrated that 30% relapsed patients respond to mTOR inhibitors. Why some lymphomas are resistant is incompletely understood. In the present study, we inhibits mTORC1 in DLBCL lines and primary tumors but minimally cytotoxic. Subsequent investigations revealed also activated eIF4E mTORC2 Akt, suggesting a potential mechanism resistance. Furthermore, knockdown component rictor, not raptor, inhibited rapamycin-induced Akt phosphorylation cells. Addition histone deacetylase inhibitor (HDI) LBH589 (LBH) overcame resistance by blocking mTOR, thus preventing activation. Further support involvement protein phosphatase PP1 LBH-mediated dephosphorylation, which could be mimicked HDAC3. This first demonstration HDI such LBH can overcome through antagonizes These results provide mechanistic rationale clinical trial combination inhibitors DLBCL.