Optimized induction of mitochondrial apoptosis for chemotherapy-free treatment of BCR-ABL+acute lymphoblastic leukemia

Abstract

BCR-ABL+acute lymphoblastic leukemia (ALL) in adults has a poor prognosis with allogeneic stem cell transplantation (SCT) considered the best curative option for suitable patients. We here characterize the curative potential of BH3-mimetics differentially targeting mitochondrial BCL2-family members using a combination therapy approach with dexamethasone and tyrosine kinase inhibitors targeting BCR-ABL. In BCR-ABL + ALL BH3-mimetics act by redistribution of mitochondrial activator BIM, which is strongly required for cytotoxicity of the BCL2-specific BH3-mimetic ABT-199, tyrosine kinase inhibitors (TKIs) and dexamethasone. BIM expression is enhanced by dexamethasone and TKIs and both synergize with ABT-199 in BCR-ABL + ALL. Triple combinations with ABT-199, dexamethasone and TKIs efficiently attenuate leukemia progression both in tissue culture and in primary cell xenotransplantation models. Notably, the dasatinib-containing combination led to treatment- and leukemia-free long-term survival in a BCR-ABL + mouse model. Finally, response to BH3-mimetics can be predicted for individual patients in a clinically relevant setting. These data demonstrate curative targeted and chemotherapy-free pharmacotherapy for BCR-ABL + ALL in a preclinical model. Clinical evaluation, in particular for patients not suitable for allogeneic SCT, is warranted.

Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia

“…To check whether the increased cytostatic effect was due to raised apoptosis signaling we performed functional apoptosis analysis on a molecular level. Matching existing literature we demonstrated elevated apoptosis levels after venetoclax incubation [ 43 , 44 , 45 ], and also following combined application by annexin V staining for flow cytometry. Venetoclax mono therapy, however, was just as effective as the combination.…”

Onco-Cardiology: Consensus Paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology

“…Nevertheless, it is important to note that combination therapies are recommended specifically for those forms of acute lymphoblastic leukaemia that are difficult to treat. The potency of dasatinib is, for example, enhanced when used in combination with M199 (venetoclax), a selective inhibitor of the B-cell lymphoma 2 (BCL-2) protein [79], and is even further enhanced in combination with dexamethasone [122]. An urgent need exists for further explore the impact of such combination therapies on the cardiovascular system.…”

Targeted anti-BCR-ABL+ ALL therapy may benefit the heart

“…We recently described a curative combined pharmacotherapy with dasatinib (DAS), venetoclax (VEN) and dexamethasone (DEX) in a humanized mouse model for BCR-ABL+ ALL (BV173-mice: BV173 ALL cell line with stable luciferase expression for bioluminescence in vivo imaging (BLI) to visualize leukemic burden in NSG mice) (1). In the present study, BV173mice developed aggressive leukemia with a mean survival of 32±2 days.…”

“…Targeted therapies are currently considered the best cost-benefit anti-cancer treatment. Accordingly, mechanism-based interventions can rationally be designed and evaluated in murine xenograft models with regard to clinically relevant end points (1,2). However, targeted anti-tumor therapies may exert unexpected on-and off-target side effects in other organ systems not affected by malignant transformation or malignant cells.…”