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Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma
Rebecca L. Goldstein, … , Leandro Cerchietti, Ari Melnick
Rebecca L. Goldstein, … , Leandro Cerchietti, Ari Melnick
Published November 3, 2015
Citation Information: J Clin Invest. 2015;125(12):4559-4571. https://doi.org/10.1172/JCI80714.
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Research Article Oncology Article has an altmetric score of 26

Pharmacoproteomics identifies combinatorial therapy targets for diffuse large B cell lymphoma

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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-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.

Authors

Rebecca L. Goldstein, Shao Ning Yang, Tony Taldone, Betty Chang, John Gerecitano, Kojo Elenitoba-Johnson, Rita Shaknovich, Wayne Tam, John P. Leonard, Gabriela Chiosis, Leandro Cerchietti, Ari Melnick

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Figure 1

teHSP90 pharmacoproteomics reveals multiple interactions with BCR pathway proteins.

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teHSP90 pharmacoproteomics reveals multiple interactions with BCR pathwa...
(A and B) Lysates from OCI-Ly1 and OCI-Ly7 cells were subjected to chemical precipitation with PU-H71 or a control chemical followed by SDS PAGE and colloidal blue staining (A). The extracted proteins were examined by LC-MS/MS as shown in B. Venn diagram is used to illustrate the numbers of overlapping and unique proteins identified by LC-MS/MS in each cell line. (C) STRING representation of the union of proteins identified in OCI-Ly1 and OCI-Ly7 PU-H71 chemical precipitations at 0.99 confidence. Enriched protein networks are indicated by text, and the BCR pathway is magnified to reveal components captured by proteomics. (D) A representation of the BCR pathway is shown. Proteins with blue shading were identified as components of the teHSP90 interactome by LC-MS/MS.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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