Blockage of BCL-XL overcomes venetoclax resistance across BCL2+lymphoid malignancies irrespective of BIM status

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F24%3A00600584" target="_blank" >RIV/86652036:_____/24:00600584 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/24:00604443 RIV/00216208:11110/24:10483793 RIV/61384399:31140/24:00060330 RIV/65269705:_____/24:00080340 RIV/00064165:_____/24:10483793

Výsledek na webu

<a href="https://ashpublications.org/bloodadvances/article/8/13/3532/516030/Blockage-of-BCL-XL-overcomes-venetoclax-resistance" target="_blank" >https://ashpublications.org/bloodadvances/article/8/13/3532/516030/Blockage-of-BCL-XL-overcomes-venetoclax-resistance</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/bloodadvances.2024012906" target="_blank" >10.1182/bloodadvances.2024012906</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Blockage of BCL-XL overcomes venetoclax resistance across BCL2+lymphoid malignancies irrespective of BIM status

Popis výsledku v původním jazyce

Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.

Název v anglickém jazyce

Blockage of BCL-XL overcomes venetoclax resistance across BCL2+lymphoid malignancies irrespective of BIM status

Popis výsledku anglicky

Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Blood Advances

ISSN

2473-9529

e-ISSN

2473-9537

Svazek periodika

8

Číslo periodika v rámci svazku

13

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

12

Strana od-do

3532-3543

Kód UT WoS článku

001294402000001

EID výsledku v databázi Scopus

2-s2.0-85195879602