Publication
The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma
Journal Paper/Review - Sep 6, 2017
Le Moigne Ronan, Chesi Marta, Bergsagel P Leif, Kraus Marianne, Driessen Christoph, Kiss von Soly Szerenke, Yakes F Michael, Wustrow David, Shawver Laura, Zhou Han-Jie, Martin Thomas G, Wolf Jeffrey L, Mitsiades Constantine S, Anderson Daniel J, Wang Jinhai, Rice Julie, Lam Christine, Aftab Blake T, Djakovic Stevan, Dhimolea Eugen, Valle Eduardo, Murnane Megan, King Emily M, Soriano Ferdie, Menon Mary-Kamala, Wu Zhi Yong, Wong Stephen T, Lee Grace J, Yao Bing, Wiita Arun P, Rolfe Mark
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PubMed
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Issn Electronic
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Brief description/objective
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 ubiquitinated 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. Mol Cancer Ther; 16(11); 2375-86. ©2017 AACR.