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

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.