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

Leukemia. 2024 Jun;38(6):1223-1235. doi: 10.1038/s41375-024-02241-7. Epub 2024 Apr 10.

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.

MeSH terms

  • Aniline Compounds* / pharmacology
  • Aniline Compounds* / therapeutic use
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Synergism
  • Humans
  • Mice
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / pathology
  • Proto-Oncogene Proteins c-bcl-2* / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2* / metabolism
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Pyrrolidines
  • Sulfonamides* / pharmacology
  • Tumor Suppressor Protein p53* / metabolism
  • Xenograft Model Antitumor Assays*
  • bcl-X Protein* / antagonists & inhibitors
  • bcl-X Protein* / metabolism
  • para-Aminobenzoates

Substances

  • bcl-X Protein
  • Tumor Suppressor Protein p53
  • Aniline Compounds
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • navitoclax
  • BCL2L1 protein, human
  • RG7388
  • TP53 protein, human
  • BCL2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Pyrrolidines
  • para-Aminobenzoates