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-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.forename: Rebecca L
authors.initials: RL
authors.lastname: Goldstein
authors.forename: Shao Ning
authors.initials: SN
authors.lastname: Yang
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.forename: Betty
authors.initials: B
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: Gerecitano
authors.forename: Kojo
authors.initials: K
authors.lastname: Elenitoba-Johnson
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D040901:Proteomics; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072377:Syk Kinase
chemical_list: D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase; D000225:Adenine