Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies

Area of Science:

• Oncology
• Molecular Biology
• Virology

Background:

• Heat shock protein 90 (Hsp90) is crucial for stabilizing oncoproteins.
• Tumor-enriched Hsp90 (teHsp90) is selectively associated with oncogenic client proteins.
• Existing Hsp90 inhibitors lack tumor-specific targeting, leading to toxicity.

Purpose of the Study:

• To investigate the efficacy of PU-H71, a selective teHsp90 inhibitor.
• To identify the molecular targets and pathways affected by PU-H71 in virus-associated lymphomas.
• To explore combination therapies involving PU-H71.

Main Methods:

• PU-H71 affinity capture coupled with proteomics to identify teHsp90 interactome.
• In vitro assays assessing apoptosis and autophagy induction.
• In vivo studies evaluating tumor response in mice.
• Testing combination therapy with a BCL2 family inhibitor.

Main Results:

• PU-H71 selectively inhibited teHsp90 in Epstein-Barr virus and KSHV-infected lymphoma cells.
• Identified viral (vFLIP) and cellular proteins in the teHsp90 interactome, including NF-κB signaling components.
• PU-H71 induced vFLIP and IKKγ degradation, NF-κB downregulation, apoptosis, and autophagy.
• PU-H71 treatment led to significant tumor regression in mice.
• Combination therapy with a BCL2 inhibitor showed synergistic activity.

Conclusions:

• PU-H71 demonstrates potent and selective inhibition of teHsp90, leading to tumor cell death and regression.
• Affinity capture reveals actionable oncogenic networks, including vFLIP and NF-κB pathways.
• PU-H71 represents a promising therapeutic agent for virus-associated lymphomas, with potential for combination therapies.