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Volume 22
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10.3390/ijms22052771
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Article

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

by
Anna Richter
*,
Elisabeth Fischer
,
Clemens Holz
,
Julia Schulze
,
Sandra Lange
,
Anett Sekora
,
Gudrun Knuebel
,
Larissa Henze
,
Catrin Roolf
,
Hugo Murua Escobar
and
Christian Junghanss
Department of Medicine, Clinic III—Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, 18057 Rostock, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(5), 2771; https://doi.org/10.3390/ijms22052771
Submission received: 5 February 2021 / Revised: 5 March 2021 / Accepted: 6 March 2021 / Published: 9 March 2021
(This article belongs to the Special Issue Novel Agents and Mechanisms in Acute Leukemias)
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Abstract

Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.
Keywords: AKT inhibition; MK-2206; acute lymphoblastic leukemia; venetoclax; apoptosis AKT inhibition; MK-2206; acute lymphoblastic leukemia; venetoclax; apoptosis

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MDPI and ACS Style

Richter, A.; Fischer, E.; Holz, C.; Schulze, J.; Lange, S.; Sekora, A.; Knuebel, G.; Henze, L.; Roolf, C.; Murua Escobar, H.; et al. Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2021, 22, 2771. https://doi.org/10.3390/ijms22052771

AMA Style

Richter A, Fischer E, Holz C, Schulze J, Lange S, Sekora A, Knuebel G, Henze L, Roolf C, Murua Escobar H, et al. Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia. International Journal of Molecular Sciences. 2021; 22(5):2771. https://doi.org/10.3390/ijms22052771

Chicago/Turabian Style

Richter, Anna, Elisabeth Fischer, Clemens Holz, Julia Schulze, Sandra Lange, Anett Sekora, Gudrun Knuebel, Larissa Henze, Catrin Roolf, Hugo Murua Escobar, and et al. 2021. "Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia" International Journal of Molecular Sciences 22, no. 5: 2771. https://doi.org/10.3390/ijms22052771

APA Style

Richter, A., Fischer, E., Holz, C., Schulze, J., Lange, S., Sekora, A., Knuebel, G., Henze, L., Roolf, C., Murua Escobar, H., & Junghanss, C. (2021). Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia. International Journal of Molecular Sciences, 22(5), 2771. https://doi.org/10.3390/ijms22052771

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