| Autor: |
Mark Rolfe, Daniel J. Anderson, Constantine S. Mitsiades, Jeffrey L. Wolf, Thomas G. Martin, Han-Jie Zhou, Laura Shawver, David Wustrow, F. Michael Yakes, Szerenke Kiss Von Soly, Christoph Driessen, Marianne Kraus, P. Leif Bergsagel, Marta Chesi, Jinhai Wang, Julie Rice, Christine Lam, Arun P. Wiita, Bing Yao, Grace J. Lee, Stephen T. Wong, Zhi Yong Wu, Mary-Kamala Menon, Ferdie Soriano, Emily M. King, Megan Murnane, Eduardo Valle, Eugen Dhimolea, Stevan Djakovic, Blake T. Aftab, Ronan Le Moigne |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1535-7163.c.6539250.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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