Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells.
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.
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.|Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
A
A
Paulus
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
S
S
Akhtar
Department of Molecular Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
T R
TR
Caulfield
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
K
K
Samuel
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
H
H
Yousaf
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Y
Y
Bashir
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
S M
SM
Paulus
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
D
D
Tran
Department of Molecular Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
R
R
Hudec
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
D
D
Cogen
Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA.
J
J
Jiang
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
B
B
Edenfield
Department of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
A
A
Novak
Department of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
S M
SM
Ansell
Department of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
T
T
Witzig
Department of Medicine, Weill Cornell Medical College, Cornell, NY, USA.
P
P
Martin
Department of Medicine, Weill Cornell Medical College, Cornell, NY, USA.
M
M
Coleman
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
V
V
Roy
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
S
S
Ailawadhi
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
K
K
Chitta
Institute for Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
S
S
Linder
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.|Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
A
A
Chanan-Khan
D000225:Adenine / Q000031:analogs & derivatives; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000008:administration & dosage*; D001597:Benzylidene Compounds / Q000008:administration & dosage*; D000069286:Bortezomib / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000072017:Deubiquitinating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D010880:Piperidines; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000235:genetics; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D001381:Azepines; D001597:Benzylidene Compounds; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C509299:USP14 protein, human; C000623193:VLX1570; C551803:ibrutinib; D000069286:Bortezomib; D000072017:Deubiquitinating Enzymes; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D000225:Adenine