Combination p53 activation and BCL-xL/BCL-2 inhibition as a therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia.
Leukemia
; 38(6): 1223-1235, 2024 Jun.
Article
de En
| MEDLINE
| ID: mdl-38600316
ABSTRACT
Due to the rarity of TP53 mutations in acute lymphoblastic leukemia (ALL), p53 re-activation by antagonism of the p53-MDM2 interaction represents a potential therapeutic strategy for the majority of ALL. Here, we demonstrate the potent antileukemic activity of the MDM2 antagonist idasanutlin in high-risk and relapsed ex vivo coculture models of TP53 wildtype ALL (n = 40). Insufficient clinical responses to monotherapy MDM2 inhibitors in other cancers prompted us to explore optimal drugs for combination therapy. Utilizing high-throughput combination screening of 1971 FDA-approved and clinically advanced compounds, we identified BCL-xL/BCL-2 inhibitor navitoclax as the most promising idasanutlin combination partner. The idasanutlin-navitoclax combination was synergistically lethal to prognostically-poor, primary-derived and primary patient blasts in ex vivo coculture, and reduced leukemia burden in two very high-risk ALL xenograft models at drug concentrations safely attained in patients; in fact, the navitoclax plasma concentrations were equivalent to those attained in contemporary "low-dose" navitoclax clinical trials. We demonstrate a preferential engagement of cell death over G1 cell cycle arrest, mechanistically implicating MCL-1-binding pro-apoptotic sensitizer NOXA. The proposed combination of two clinical-stage compounds independently under clinical evaluation for ALL is of high clinical relevance and warrants consideration for the treatment of patients with high-risk and relapsed ALL.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Sulfonamides
/
Protéine p53 suppresseur de tumeur
/
Protéines proto-oncogènes c-bcl-2
/
Tests d'activité antitumorale sur modèle de xénogreffe
/
Protéine bcl-X
/
Leucémie-lymphome lymphoblastique à précurseurs B et T
/
Dérivés de l'aniline
Limites:
Animals
/
Humans
Langue:
En
Journal:
Leukemia
Sujet du journal:
HEMATOLOGIA
/
NEOPLASIAS
Année:
2024
Type de document:
Article
Pays d'affiliation:
Royaume-Uni