Reference Detail

Ref Type Journal Article
PMID (27813535)
Authors Paulus A, Akhtar S, Caulfield TR, Samuel K, Yousaf H, Bashir Y, Paulus SM, Tran D, Hudec R, Cogen D, Jiang J, Edenfield B, Novak A, Ansell SM, Witzig T, Martin P, Coleman M, Roy V, Ailawadhi S, Chitta K, Linder S, Chanan-Khan A
Title Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells.
Journal Blood cancer journal
Vol 6
Issue 11
Date 2016 Nov 04
URL
Abstract Text The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics. Here we provide a comprehensive preclinical report on the anti-WM activity of VLX1570, a novel small-molecule inhibitor of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5). Both DUBs reside in the 19 S proteasome cap and their inhibition by VLX1570 results in rapid and tumor-specific apoptosis in bortezomib- or ibrutinib-resistant WM cells. Notably, treatment of WM cells with VLX1570 downregulated BCR-associated elements BTK, MYD88, NFATC, NF-κB and CXCR4, the latter whose dysregulated function is linked to ibrutinib resistance. VLX1570 administered to WM-xenografted mice resulted in decreased tumor burden and prolonged survival (P=0.0008) compared with vehicle-treated mice. Overall, our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant WM and carries a high potential for clinical translation.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
VLX1570 VLX1570 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
VLX1570 VLX1570 is a small-molecule that inhibits USP14 and UCHL5, which may result in increased tumor cell death (PMID: 27813535).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown lymphoplasmacytic lymphoma not applicable VLX1570 Preclinical - Cell line xenograft Actionable In a preclinical study, VLX1570 induced apoptosis in Waldenstrom macroglobulinemia (WM) cell lines, including Velcade (bortezomib)-resistant cell lines, and primary WM cells in culture, and reduced tumor growth and increased survival in WM cell line xenograft models (PMID: 27813535). 27813535
Unknown unknown lymphoblastic lymphoma not applicable Ibrutinib + VLX1570 Preclinical - Cell culture Actionable In a preclinical study, the combination of Imbruvica (ibrutinib) and VLX1570 worked synergistically to reduce viability of an Imbruvica (ibrutinib)-resistant Waldenstrom macroglobulinemia cell line in culture (PMID: 27813535). 27813535