Abstract
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.
Highlights
Waldenstrom macroglobulinemia (WM) is an indolent yet incurable B-cell lymphoma, in which aberrant B-cell receptor (BCR), Tolllike receptor and MYD88 signaling cooperatively drive tumor cell survival
These findings affirmed that both proteasome-associated deubiquitinating enzymes (DUBs) are upregulated and their expression is increased in human WM cells
Bortezomib has been shown to downregulate the expression of BTK as well as other BCR-signalosome components such as MYD88.38,39 We addressed the question of whether this phenomenon could be elicited by blocking the DUB (USP14/ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5)) machinery (USP14/UCHL5) of the 19 S proteasome with VLX1570
Summary
Waldenstrom macroglobulinemia (WM) is an indolent yet incurable B-cell lymphoma, in which aberrant B-cell receptor (BCR), Tolllike receptor and MYD88 signaling cooperatively drive tumor cell survival. This observation has been clinically exploited with the BTK inhibitor, ibrutinib. To sustain BCR/Toll-like receptor-driven growth and maintain optimal cellular homeostasis, WM cells upregulate proteasome function.[10,11] Clinical benefit derived through proteasome inhibitor (PI) therapy has been clearly established in several B-cell cancers, including WM.[12] PI-based management of disease yields responses in ~ 85% of relapsed/refractory WM patients.[13,14,15,16]
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