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PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

Kallesh D Jayappa1,2,3, Brian Tran4, Vicki L Gordon1,2

  • 1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia, USA.

The Journal of Clinical Investigation
|May 11, 2023
PubMed

Insights

Targeted therapies for chronic lymphocytic leukemia (CLL) face resistance due to antiapoptotic proteins. A novel small-molecule activator of protein phosphatase 2A (SMAP) effectively targets these resistant CLL cells, offering a new therapeutic avenue.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Targeted therapies like venetoclax have transformed chronic lymphocytic leukemia (CLL) treatment.
  • Persister CLL cells exhibit resistance by overexpressing antiapoptotic proteins, hindering apoptosis.
  • This resistance is linked to pre-mitochondrial apoptosis restriction involving Bax/Bak proteins.

Purpose of the Study:

  • To investigate the mechanism of apoptosis resistance in multidrug-resistant CLL cells.
  • To identify novel therapeutic strategies to overcome treatment resistance in CLL.
  • To evaluate the efficacy of a small-molecule activator of protein phosphatase 2A (SMAP) in targeting resistant CLL cells.

Main Methods:

  • Co-immunoprecipitation analyses using selective BH domain antagonists.
  • Assessment of apoptosis induction by SMAP (DT-061) in various cancer cell lines and CLL samples.
  • Xenograft mouse model studies with wild-type and Bax/Bak double-knockout multidrug-resistant CLL cells.

Main Results:

  • Multidrug-resistant CLL cells showed apoptosis restriction due to insufficient Bax/Bak activation.
  • The proapoptotic protein Bim was sequestered by upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2).
  • SMAP (DT-061) induced cytotoxicity and apoptosis in resistant CLL cells, independent of Bax/Bak, by activating mitochondrial permeability transition pores.

Conclusions:

  • A novel mechanism of apoptosis resistance in CLL involving Bax/Bak restriction was identified.
  • SMAP (DT-061) represents a promising therapeutic agent for overcoming venetoclax resistance in CLL.
  • Targeting protein phosphatase 2A (PP2A) offers a pharmacologically tractable approach to deplete resistant CLL cell reservoirs.
Keywords:
Apoptosis pathwaysCancerCell BiologyOncologyPhosphoprotein phosphatases

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