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.
Highlights
Introduction published maps and institutional affilTherapeutic regimens for acute lymphoblastic leukemia (ALL) have improved during the past decades
Incubation with MK-2206 induced an initial decrease in AKT activity in all cell lines which was detectable after 30 min incubation already, even at concentrations as low as 0.5 μM
We evaluated the effects of the selective pan–AKT inhibitor MK-2206 on B-cell precursor ALL (B-ALL) cell lines and primary blasts cultivated in a protective bone marrow microenvironment
Summary
Introduction published maps and institutional affilTherapeutic regimens for acute lymphoblastic leukemia (ALL) have improved during the past decades. Resistance to routinely used chemotherapeutic agents is frequently observed and results in even worse outcomes in relapsed ALL patients [2]. This demonstrates the urgent need for novel drugs and targeted treatment strategies aiming at the individual resistanceinducing structures. In B-cell precursor ALL (B-ALL) a large variety of factors like mutations, chromosomal translocations or epigenetic dysregulation contribute to tumorigenesis [3,4]. Those molecular aberrations result in aberrant proliferation and apoptosis signaling, leading to increased tumor cell growth and survival. The PI3K/AKT pathway is a key signaling cascade involved in both processes and frequently dysregulated in several hematological iations
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