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Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell

Clare M Adams1, Amanda McBride1,2, Peter Michener1

  • 1Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, 233 South 10th St., Philadelphia, PA 19107, USA.

Cancers
|June 19, 2024
PubMed

Insights

Venetoclax resistance in diffuse large B-cell lymphoma (DLBCL) can be overcome by targeting oxidative phosphorylation or other pathways. This study identifies new strategies to treat venetoclax-resistant B-cell lymphomas.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Single-agent venetoclax (BCL2 inhibitor) shows limited efficacy in diffuse large B-cell lymphoma (DLBCL) due to BCL2-independent survival mechanisms.
  • Understanding resistance pathways is crucial for developing effective treatment strategies against DLBCL.

Purpose of the Study:

  • To investigate mechanisms of acquired and intrinsic venetoclax resistance in DLBCL.
  • To identify novel therapeutic targets and combination strategies for overcoming venetoclax resistance in DLBCL and other B-cell lymphomas.

Main Methods:

  • Generation and evaluation of acquired venetoclax-resistant DLBCL cell lines alongside intrinsically resistant and sensitive lines.
  • RNA-sequencing, drug/compound screening, and assessment of drug sensitivity in patient samples.
  • Inhibition of specific pathways including oxidative phosphorylation, IDH2, transcription, B-cell receptor signaling, and histone deacetylases.

Main Results:

  • Distinct BCL2 family alterations were observed in acquired versus intrinsic venetoclax resistance.
  • Venetoclax-resistant DLBCL cells, including TP53-mutated cases, showed a dependency on oxidative phosphorylation.
  • Inhibition of mitochondrial electron transport chain complex I and IDH2 induced cell death in resistant DLBCL.
  • Acquired and intrinsic resistant cells were sensitive to inhibitors of transcription, B-cell receptor signaling, and class I histone deacetylases.
  • These strategies demonstrated efficacy in DLBCL, follicular, and marginal zone lymphoma patient samples.

Conclusions:

  • Multiple pathways can be targeted to circumvent diverse venetoclax resistance mechanisms in DLBCL.
  • Targeting oxidative phosphorylation, IDH2, transcription, B-cell receptor signaling, or histone deacetylases offers potential therapeutic avenues for venetoclax-resistant B-cell lymphomas.
  • These findings identify critical pathways for future clinical investigation in B-cell malignancies.
Keywords:
B-cell lymphomaBCL2IDH2mitochondrial electron transport chain (ETC)venetoclax/ABT-199 resistance

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