Combination p53 activation and BCL-x_L/BCL-2 inhibition as a therapeutic strategy in high-risk and relapsed acute lymphoblastic leukemia.

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-x_L/BCL-2 inhibitor navitoclax as the most promising idasanutlin combination partner. The idasanutlin-navitoclax combination was synergistically lethal

SUBMITTER: Bell HL 

PROVIDER: S-EPMC11147763 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature