Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Refractory cancers like activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) require combination targeted therapies for durable responses.
• Tumor-enriched heat shock protein 90 (teHSP90) is a potential therapeutic target in various cancers.
• The B cell receptor (BCR) signaling pathway is crucial in ABC DLBCL pathogenesis.

Purpose of the Study:

• To investigate the role of teHSP90 in BCR signaling in ABC DLBCL.
• To evaluate the efficacy of PU-H71, a teHSP90 inhibitor, in combination with ibrutinib, a BCR pathway inhibitor, for treating ABC DLBCL.

Main Methods:

• Pharmacoproteomics approach using PU-H71 to map teHSP90 interactome in DLBCL cell lines.
• Functional assays to assess the impact of PU-H71 on BCR signaling components (SYK, BTK), calcium flux, and NF-κB signaling.
• In vitro and in vivo studies evaluating the combination of PU-H71 and ibrutinib in lymphoma models.

Main Results:

• teHSP90 complexes were found to be enriched with components of the BCR signalosome.
• PU-H71 treatment inhibited BCR signaling, calcium flux, and NF-κB signaling, leading to growth arrest in ABC DLBCL cells.
• The combination of PU-H71 and ibrutinib demonstrated synergistic killing of lymphoma cells and xenografts with no significant toxicity.

Conclusions:

• teHSP90 plays a role in facilitating BCR signaling dynamics in ABC DLBCL.
• Pharmacoproteomics-guided rational combination of PU-H71 and ibrutinib offers a potent therapeutic strategy for ABC DLBCL.
• This combination therapy holds promise for improving treatment outcomes in patients with ABC DLBCL.