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Synergistic activity of combined inhibition of anti-apoptotic molecules in B-cell precursor ALL

Felix Seyfried1, Felix Uli Stirnweiß1,2, Alexandra Niedermayer1,2

  • 1Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.

Leukemia
|January 15, 2022
PubMed

Insights

Targeting BCL-2 is a promising leukemia treatment, but resistance occurs. Combining BCL-2 inhibitors with BCL-XL or MCL-1 inhibitors overcomes resistance by exploiting protein redundancy, enhancing anti-leukemia effects.

Area of Science:

  • Molecular oncology
  • Cancer therapeutics
  • Hematologic malignancies

Background:

  • BCL-2 family proteins regulate cell survival in B-cell malignancies.
  • Targeting BCL-2 is a strategy for precursor B-cell acute lymphoblastic leukemia (ALL).
  • Redundancy among BCL-2, BCL-XL, and MCL-1 can limit single-agent efficacy.

Purpose of the Study:

  • To investigate the efficacy of combining BCL-2 inhibitors with BCL-XL or MCL-1 inhibitors in ALL.
  • To explore the mechanisms of resistance and functional redundancy within the BCL-2 protein family.
  • To evaluate the in vivo anti-leukemia activity of combination therapies.

Main Methods:

  • Analysis of BH3-mimetics targeting BCL-XL and MCL-1 in combination with venetoclax (BCL-2 inhibitor).
  • Assessment of drug sensitivity in ALL cell lines and patient-derived xenografts (PDXs).
  • Functional analysis using BH3-profiling and protein complex analysis.
  • In vivo evaluation of combination therapy in a pre-clinical PDX model.

Main Results:

  • Heterogeneous sensitivity to single inhibitors was observed in ALL models.
  • Venetoclax-resistant leukemias showed sensitivity to MCL-1 or BCL-XL inhibitors, indicating functional substitution.
  • Co-inhibition of BCL-2 with MCL-1 or BCL-XL induced synergistic apoptosis.
  • Venetoclax-treated ALL cells demonstrated dependency on MCL-1 and BCL-XL.
  • Combination of venetoclax and S63845 (MCL-1 inhibitor) showed enhanced anti-leukemia activity in vivo.

Conclusions:

  • MCL-1 and BCL-XL represent an Achilles' heel in BCL-2-inhibited ALL cells.
  • Combination therapy targeting BCL-2 and either MCL-1 or BCL-XL overcomes resistance.
  • This study provides a rationale for combination treatments in ALL, supported by pre-clinical data and ongoing clinical trials.

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