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

Pei-Jie Shi,Wen-Jun Weng,Kang-Yu Lin,Jian-Pei Fang,Lu-Hong Xu

doi:10.1186/s13045-016-0241-x

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.

Highlights

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells in both children and adults
focal adhesion kinase (FAK) was highly expressed in leukemia cells of patients with ALL We examined whether FAK was activated in leukemia cells from patients and showed by Western blot analysis (Fig. 1a(i)) and confirmed by quantitative realtime polymerase chain reaction (PCR) analysis (Fig. 1a(ii)) that FAK protein expression is higher in leukemia cells from patients (n = 10) than in lymphocytes from normal volunteers (n = 3)
Western blot was used to analyze REH-empty vector cells or REH cells knocked down with FAK short-hairpin RNA and treated with or without rapamycin 100 nM for 10 h

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells in both children and adults. 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. 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. Evidence indicates that the phosphatidylinositol 3-kinase (PI3K), Akt, mTOR signaling pathway (PI3K/Akt/ mTOR) is dysregulated in hematologic malignancies and abnormally activated in childhood ALL. Combination therapeutic strategies of using rapamycin with focal adhesion kinase (FAK) down-regulation may address the problem of resistance to mTOR-targeted monotherapy and improve the treatment effect

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