Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells

Aneel Paulus, S. Akhtar, Thomas Caulfield, K. Samuel, H. Yousaf, Y. Bashir, S. M. Paulus, D. Tran, R. Hudec, D. Cogen, J. Jiang, B. Edenfield, Anne J Novak, Stephen Maxted Ansell, Thomas Elmer Witzig, P. Martin, M. Coleman, Vivek Roy, Sikander Ailawadhi, K. ChittaS. Linder, Asher A Chanan Khan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere492
JournalBlood Cancer Journal
Volume6
Issue number11
DOIs
StatePublished - Nov 4 2016

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Ubiquitin-Specific Proteases
Waldenstrom Macroglobulinemia
Hydrolases
Ubiquitin
Isoenzymes
Neoplasms
Proteasome Endopeptidase Complex
B-Lymphocytes
Survival
PCI 32765
Bortezomib
Deubiquitinating Enzymes
Therapeutics
Tumor Burden
Homeostasis
Up-Regulation
Down-Regulation

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells. / Paulus, Aneel; Akhtar, S.; Caulfield, Thomas; Samuel, K.; Yousaf, H.; Bashir, Y.; Paulus, S. M.; Tran, D.; Hudec, R.; Cogen, D.; Jiang, J.; Edenfield, B.; Novak, Anne J; Ansell, Stephen Maxted; Witzig, Thomas Elmer; Martin, P.; Coleman, M.; Roy, Vivek; Ailawadhi, Sikander; Chitta, K.; Linder, S.; Chanan Khan, Asher A.

In: Blood Cancer Journal, Vol. 6, No. 11, e492, 04.11.2016.

Research output: Contribution to journalArticle

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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.",
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AU - Paulus, Aneel

AU - Akhtar, S.

AU - Caulfield, Thomas

AU - Samuel, K.

AU - Yousaf, H.

AU - Bashir, Y.

AU - Paulus, S. M.

AU - Tran, D.

AU - Hudec, R.

AU - Cogen, D.

AU - Jiang, J.

AU - Edenfield, B.

AU - Novak, Anne J

AU - Ansell, Stephen Maxted

AU - Witzig, Thomas Elmer

AU - Martin, P.

AU - Coleman, M.

AU - Roy, Vivek

AU - Ailawadhi, Sikander

AU - Chitta, K.

AU - Linder, S.

AU - Chanan Khan, Asher A

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