TitlePharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma.
Publication TypeJournal Article
Year of Publication2015
AuthorsGoldstein, Rebecca L., Yang Shao Ning, Taldone Tony, Chang Betty, Gerecitano John, Elenitoba-Johnson Kojo, Shaknovich Rita, Tam Wayne, Leonard John P., Chiosis Gabriela, Cerchietti Leandro, and Melnick Ari
JournalJ Clin Invest
Volume125
Issue12
Pagination4559-71
Date Published2015 Nov 03
ISSN1558-8238
KeywordsAdenine, Agammaglobulinaemia Tyrosine Kinase, Antineoplastic Combined Chemotherapy Protocols, Benzodioxoles, Cell Line, Tumor, HSP90 Heat-Shock Proteins, Humans, Intracellular Signaling Peptides and Proteins, Lymphoma, Large B-Cell, Diffuse, Piperidines, Protein-Tyrosine Kinases, Proteomics, Purines, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, Signal Transduction, Syk Kinase
Abstract

<p>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-κB 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. </p>

DOI10.1172/JCI80714
Alternate JournalJ Clin Invest
PubMed ID26529251
PubMed Central IDPMC4665772
Grant ListUL1 RR024996 / RR / NCRR NIH HHS / United States
R01 CA155226 / CA / NCI NIH HHS / United States
R21 CA158609 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P01 CA186866 / CA / NCI NIH HHS / United States
5 F31 CA174239-02 / CA / NCI NIH HHS / United States
U01 AG032969 / AG / NIA NIH HHS / United States
R01 CA172546 / CA / NCI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
F31 CA174239 / CA / NCI NIH HHS / United States