The pan-BCL-2-blocker obatoclax (GX15-070) and the PI3-kinase/mTOR-inhibitor BEZ235 produce cooperative growth-inhibitory effects in ALL cells

Gabriele Stefanzl; Daniela Berger; Sabine Cerny-Reiterer; Katharina Blatt; Gregor Eisenwort; Wolfgang R Sperr; Gregor Hoermann; Karin Lind; Alexander W Hauswirth; Peter Bettelheim; Heinz Sill; Junia V Melo; Ulrich Jäger; Peter Valent

doi:10.18632/oncotarget.18810

The pan-BCL-2-blocker obatoclax (GX15-070) and the PI3-kinase/mTOR-inhibitor BEZ235 produce cooperative growth-inhibitory effects in ALL cells

Oncotarget. 2017 Jun 28;8(40):67709-67722. doi: 10.18632/oncotarget.18810. eCollection 2017 Sep 15.

Authors

Gabriele Stefanzl^#^{1

2}, Daniela Berger^#¹, Sabine Cerny-Reiterer^{1

2}, Katharina Blatt^{1

2}, Gregor Eisenwort^{1

2}, Wolfgang R Sperr^{1

2}, Gregor Hoermann^{2

3}, Karin Lind⁴, Alexander W Hauswirth^{1

2}, Peter Bettelheim⁵, Heinz Sill⁴, Junia V Melo⁶, Ulrich Jäger^{1

2}, Peter Valent^{1

2}

Affiliations

¹ Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.
² The Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
³ Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
⁴ Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria.
⁵ Division of Laboratory Medicine, Elisabethinen Hospital Linz, Linz, Austria.
⁶ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.

^# Contributed equally.

Abstract

Acute lymphoblastic leukemia (ALL) is characterized by leukemic expansion of lymphoid blasts in hematopoietic tissues. Despite improved therapy only a subset of patients can be cured. Therefore, current research is focusing on new drug-targets. Members of the BCL-2 family and components of the PI3-kinase/mTOR pathway are critically involved in the regulation of growth and survival of ALL cells. We examined the effects of the pan-BCL-2 blocker obatoclax and the PI3-kinase/mTOR-inhibitor BEZ235 on growth and survival of ALL cells. In ³H-thymidine uptake experiments, both drugs suppressed the in vitro proliferation of leukemic cells in all patients with Philadelphia chromosome-positive (Ph⁺) ALL and Ph^- ALL (obatoclax IC₅₀: 0.01-5 μM; BEZ235, IC₅₀: 0.01-1 μM). Both drugs were also found to produce growth-inhibitory effects in all Ph⁺ and all Ph^- cell lines tested. Moreover, obatoclax and BEZ235 induced apoptosis in ALL cells. In drug-combination experiments, obatoclax and BEZ235 exerted synergistic growth-inhibitory effects on ALL cells. Finally, we confirmed that ALL cells, including CD34⁺/CD38^- stem cells and all cell lines express transcripts for PI3-kinase, mTOR, BCL-2, MCL-1, and BCL-xL. Taken together, this data shows that combined targeting of the PI3-kinase/mTOR-pathway and BCL-2 family-members is a potent approach to counteract growth and survival of ALL cells.

Keywords: ALL; BCL-2 family members; PI3-Kinase; mTOR; targeting-concepts.