Combined BCL-2 and PI3K/AKT Pathway Inhibition in KMT2A-Rearranged Acute B-Lymphoblastic Leukemia Cells

Abstract

Numerous hematologic neoplasms, including acute B-lymphoblastic leukemia (B-ALL), are characterized by overexpression of anti-apoptotic BCL-2 family proteins. Despite the high clinical efficacy of the specific BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), dose limitation and resistance argue for the early exploration of rational combination strategies. Recent data indicated that BCL-2 inhibition in B-ALL with KMT2A rearrangements is a promising intervention option; however, combinatorial approaches have not been in focus so far. The PI3K/AKT pathway has emerged as a possible target structure due to multiple interactions with the apoptosis cascade as well as relevant dysregulation in B-ALL. Herein, we demonstrate for the first time that combined BCL-2 and PI3K/AKT inhibition has synergistic anti-proliferative effects on B-ALL cell lines. Of note, all tested combinations (venetoclax + PI3K inhibitors idelalisib or BKM-120, as well as AKT inhibitors MK-2206 or perifosine) achieved comparable anti-leukemic effects. In a detailed analysis of apoptotic processes, among the PI3K/AKT inhibitors only perifosine resulted in an increased rate of apoptotic cells. Furthermore, the combination of venetoclax and perifosine synergistically enhanced the activity of the intrinsic apoptosis pathway. Subsequent gene expression studies identified the pro-apoptotic gene BBC3 as a possible player in synergistic action. All combinatorial approaches additionally modulated extrinsic apoptosis pathway genes. The present study provides rational combination strategies involving selective BCL-2 and PI3K/AKT inhibition in B-ALL cell lines. Furthermore, we identified a potential mechanistic background of the synergistic activity of combined venetoclax and perifosine application.

Combination fedratinib and venetoclax has activity against human B-ALL with high FLT3 expression

“…However, maximal effects were seen when combining venetoclax with chemotherapy (20). Other studies demonstrating efficacy of venetoclax in B-ALL include combining with MCL-1 inhibitors (21, 22), monoclonal antibodies such as daratumumab in relapsed/refractory B-ALL (23), AKT inhibitors (24, 25), MDM2 inhibitors (26), and also with BCR-ABL inhibitors (27). No prior studies have looked at the combination of JAK2 inhibitors with venetoclax in B-ALL.…”

Recent Updates in Venetoclax Combination Therapies in Pediatric Hematological Malignancies

“…Apart from the effect on pathological cells, another research aim was to check whether VTX has a cytotoxic effect on healthy cells. No harmful effects on normal PB cells were noted either in monotherapy [91,92] or in combination with other drugs [91,93].…”

Características da ação dos oxisteróis 7-ketocholesterol e colestane-3,5,6-triol nas proteínas transportadoras ABCs e LRP das células-tronco mesenquimais derivadas de medula óssea de pacientes com leucemia mieloide aguda

“…De forma semelhante, a proteína survivina no citoplasma atua como repressora da apoptose, no núcleo ela está associada a tubulina e participa da divisão celular. Ambas as proteínas estão associadas a resistência a quimioterapia e mecanismos de escape de morte celular em células tumorais (235)(236)(237). Aqui, cabe destacar que em CTM-D a quantidade de survivina citoplasmática foi elevada, e que esse pode ser um mecanismo de sobrevivência das CTMs derivadas de pacientes diagnosticados com LMA, uma vez que a survivina interage com mais várias vias de proliferação e moléculas de superfície (238,239).…”