The p97 inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of multiple myeloma

Ronan Le Moigne, Blake T. Aftab, Stevan Djakovic, Eugen Dhimolea, Eduardo Valle, Megan Murnane, Emily M. King, Ferdie Soriano, Mary Kamala Menon, Zhi Yong Wu, Stephen T. Wong, Grace J. Lee, Bing Yao, Arun P. Wiita, Christine Lam, Julie Rice, Jinhai Wang, Marta Chesi, Peter Leif Bergsagel, Marianne KrausChristoph Driessen, Szerenke Kiss Von Soly, F. Michael Yakes, David Wustrow, Laura Shawver, Han Jie Zhou, Thomas G. Martin, Jeffrey L. Wolf, Constantine S. Mitsiades, Daniel J. Anderson, Mark Rolfe

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquiti-nated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma.

Original languageEnglish (US)
Pages (from-to)2375-2386
Number of pages12
JournalMolecular Cancer Therapeutics
Volume16
Issue number11
DOIs
StatePublished - Nov 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Le Moigne, R., Aftab, B. T., Djakovic, S., Dhimolea, E., Valle, E., Murnane, M., King, E. M., Soriano, F., Menon, M. K., Wu, Z. Y., Wong, S. T., Lee, G. J., Yao, B., Wiita, A. P., Lam, C., Rice, J., Wang, J., Chesi, M., Bergsagel, P. L., ... Rolfe, M. (2017). The p97 inhibitor CB-5083 is a unique disrupter of protein homeostasis in models of multiple myeloma. Molecular Cancer Therapeutics, 16(11), 2375-2386. https://doi.org/10.1158/1535-7163.MCT-17-0233