Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma Journal Article

Authors: Goldstein, R. L.; Yang, S. N.; Taldone, T.; Chang, B.; Gerecitano, J.; Elenitoba-Johnson, K.; Shaknovich, R.; Tam, W.; Leonard, J. P.; Chiosis, G.; Cerchietti, L.; Melnick, A.
Article Title: Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma
Abstract: Rationally designed combinations of targeted therapies for refractory cancers, such as activated B cell-like diffuse large B cell lymphoma (ABC DLBCL), are likely required to achieve potent, durable responses. Here, we used a pharmacoproteomics approach to map the interactome of a tumor-enriched isoform of HSP90 (teHSP90). Specifically, we chemically precipitated teHSP90-client complexes from DLBCL cell lines with the small molecule PU-H71 and found that components of the proximal B cell receptor (BCR) signalosome were enriched within teHSP90 complexes. Functional assays revealed that teHSP90 facilitates BCR signaling dynamics by enabling phosphorylation of key BCR signalosome components, including the kinases SYK and BTK. Consequently, treatment of BCR-dependent ABC DLBCL cells with PU-H71 attenuated BCR signaling, calcium flux, and NF-êB signaling, ultimately leading to growth arrest. Combined exposure of ABC DLBCL cell lines to PU-H71 and ibrutinib, a BCR pathway inhibitor, more potently suppressed BCR signaling than either drug alone. Correspondingly, PU-H71 combined with ibrutinib induced synergistic killing of lymphoma cell lines, primary human lymphoma specimens ex vivo, and lymphoma xenografts in vivo, without notable toxicity. Together, our results demonstrate that a pharmacoproteome-driven rational combination therapy has potential to provide more potent BCR-directed therapy for ABC DLCBL patients.
Keywords: controlled study; human tissue; protein phosphorylation; functional assessment; unclassified drug; human cell; cancer combination chemotherapy; drug potentiation; antineoplastic agent; complex formation; immunoglobulin enhancer binding protein; drug potency; proteomics; xenograft; heat shock protein 90; large cell lymphoma; ex vivo study; cell killing; growth disorder; calcium transport; calcium signaling; pu h 71; b lymphocyte receptor; lymphoma cell line; protein kinase syk; bruton tyrosine kinase; ibrutinib; human; priority journal; article
Journal Title: Journal of Clinical Investigation
Volume: 125
Issue: 12
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2015-12-01
Start Page: 4559
End Page: 4571
Language: English
DOI: 10.1172/JCI80714
PROVIDER: scopus
PMCID: PMC4665772
PUBMED: 26529251
Notes: Article -- Export Date: 7 January 2016 -- 4559 -- Source: Scopus
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MSK Authors
  1. Gabriela Chiosis
    218 Chiosis
  2. Tony Taldone
    74 Taldone