Synergism between the mTOR inhibitor rapamycin and FAK down-regulation in the treatment of acute lymphoblastic leukemia

Abstract

BackgroundAcute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells in both children and adults. Although improvements in contemporary therapy and development of new treatment strategies have led to dramatic increases in the cure rate in children with ALL, the relapse rate remains high and the prognosis of relapsed childhood ALL is poor. Molecularly targeted therapies have emerged as the leading treatments in cancer therapy. Multi-cytotoxic drug regimens have achieved success, yet many studies addressing targeted therapies have focused on only one single agent. In this study, we attempted to investigate whether the effect of the mammalian target of rapamycin (mTOR) inhibitor rapamycin is synergistic with the effect of focal adhesion kinase (FAK) down-regulation in the treatment of ALL.MethodsThe effect of rapamycin combined with FAK down-regulation on cell proliferation, the cell cycle, and apoptosis was investigated in the human precursor B acute lymphoblastic leukemia cells REH and on survival time and leukemia progression in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model.ResultsWhen combined with FAK down-regulation, rapamycin-induced suppression of cell proliferation, G0/G1 cell cycle arrest, and apoptosis were significantly enhanced. In addition, REH cell-injected NOD/SCID mice treated with rapamycin and a short-hairpin RNA (shRNA) to down-regulate FAK had significantly longer survival times and slower leukemia progression compared with mice injected with REH-empty vector cells and treated with rapamycin. Moreover, the B-cell CLL/lymphoma-2 (BCL-2) gene family was shown to be involved in the enhancement, by combined treatment, of REH cell apoptosis.ConclusionsFAK down-regulation enhanced the in vitro and in vivo inhibitory effects of rapamycin on REH cell growth, indicating that the simultaneous targeting of mTOR- and FAK-related pathways might offer a novel and powerful strategy for treating ALL.

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

“…Unfortunately, most of these lines were not profiled for drug sensitivity in the original CCLE study. However, several studies have recently emerged demonstrating the potential of mTOR inhibitors as therapeutics for ALL, especially in synergy with other agents ( Iacovelli et al, 2015 ; Shi et al, 2016 ; Tasian et al, 2017 ; Witzig et al, 2015 ). One recent study details the synergy between an mTOR inhibitor and a CDK4/6 inhibitor in T-ALL, hitting two of the three classes of compounds that are anti-connected to the NSD2:p.Glu1099Lys set of lines.…”

Targeting mTOR in Acute Lymphoblastic Leukemia

“…This suggests an important role of this cytokine in the control of mTOR activity in B-ALL cells [175]. Moreover, rapamycin has been reported to be synergistic with focal adhesion kinase (FAK) down-regulation in REH cells with significant down-regulation of cell growth, cell cycle and apoptosis [7]. CCI-779 significantly decreased survival and induced apoptosis of lymphoblasts from Ph − B-ALL adult patients co-cultured with bone marrow stromal cells.…”

“…ALL is an aggressive malignancy of lymphoid progenitor cells in both pediatric and adult patients. In adults, 75% of cases develop from precursors of the B-cell lineage, the others consisting of malignant T-cell precursors [5,6,7,8,9,10]. T-ALL is also found in a range of 15% to 20% in children, affecting boys more than girls.…”

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations

“…Unfortunately, most of these lines were not profiled for drug sensitivity in the original CCLE study. However, several studies have recently emerged demonstrating the potential of mTOR inhibitors as therapeutics for ALL, especially in synergy with other agents (Iacovelli et al, 2015;Shi et al, 2016;Tasian et al, 2017;Witzig et al, 2015). One recent study details the synergy between an mTOR inhibitor and a CDK4/6 inhibitor in T-ALL, hitting two of the three classes of compounds that are anti-connected to the NSD2 E1099K set of lines.…”