mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells

Abstract

High activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis in pre-B-cell acute lymphoblastic leukemia (B-ALL), suggesting that inhibiting mTOR might be clinically useful. However, emerging data indicate that mTOR inhibitors are most effective when combined with other target agents. One strategy is to combine with histone deacetylase (HDAC) inhibitors, since B-ALL is often characterized by epigenetic changes that silence the expression of pro-apoptotic factors. Here we tested combinations of mTOR and pan-HDAC inhibitors on B-ALL cells, including both Philadelphia chromosome-positive (Ph+) and non-Ph cell lines. We found that mTOR kinase inhibitors (TOR-KIs) synergize with HDAC inhibitors to cause apoptosis in B-ALL cells and the effect is greater when compared to rapamycin plus HDAC inhibitors. The combination of TOR-KIs with the clinically approved HDAC inhibitor vorinostat increased apoptosis in primary pediatric B-ALL cells in vitro. Mechanistically, TOR-KI and HDAC inhibitor combinations increased expression of pro-death genes, including targets of the Forkhead Box O (FOXO) transcription factors, and increased sensitivity to apoptotic triggers at the mitochondria. These findings suggest that targeting epigenetic factors can unmask the cytotoxic potential of TOR-KIs towards B-ALL cells.

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…ERCC1 and p53 were reported to have a predictive role for the efficacy of combined panobinostat and cisplatin treatment (Fischer et al 2015). HDAC inhibitions could also overcome resistance to mTOR inhibitors (e.g., everolimus, temsirolimus, sirolimus and ridaforolimus) in advanced solid tumors or lymphoma (Dong et al 2013; Beagle et al 2015; Zibelman et al 2015). …”

Control of B lymphocyte development and functions by the mTOR signaling pathways

“…For example, dual treatment of xenograft ALL models with sirolimus and methotrexate decreases levels of dihydrofolate reductase, a protein which confers methotrexate resistance by rescuing DNA biosynthesis [135]. Similarly, combinations of mTOR and histone deacetylase inhibitors (HDACs) have shown efficacy in preclinical models of ALL [136]. Dual inhibition of mTOR and the anti-apoptotic protein Bcl2 also increased death of ALL cells by repressing Mcl1 expression [137].…”

Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

“…We have previously shown sensitivity and drug synergy for the combination of mTOR(mTORi) and histone deacetylase inhibitors(HDACi) in multiple myeloma(MM) cells isolated from patients as well as in genetically diverse sets of human MM, Burkitt’s lymphoma (BL), and mouse plasmacytoma cell lines(4). Preclinical findings have been reported for additional malignancies(5,6) and clinical activity has been found in an early phase trial of everolimus (mTORi) and panobinostat (HDACi) in patients with relapsed lymphoma(7). Panobinostat in combination with bortezomib and dexamethasone has been approved for use in treatment-refractory myeloma patients(8).…”