Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma.

Abstract

Three proteasome inhibitors have garnered regulatory approvals in various multiple myeloma settings; but drug resistance is an emerging challenge, prompting interest in blocking upstream components of the ubiquitin-proteasome pathway. One such attractive target is the E1 ubiquitin-activating enzyme (UAE); we therefore evaluated the activity of TAK-243, a novel and specific UAE inhibitor. TAK-243 potently suppressed myeloma cell line growth, induced apoptosis, and activated caspases while decreasing the abundance of ubiquitin-protein conjugates. This was accompanied by stabilization of many short-lived proteins, including p53, myeloid cell leukemia 1 (MCL-1), and c-MYC, and activation of the activating transcription factor 6 (ATF-6), inositol-requiring enzyme 1 (IRE-1), and protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) arms of the ER stress response pathway, as well as oxidative stress. UAE inhibition showed comparable activity against otherwise isogenic cell lines with wild-type (WT) or deleted p53 despite induction of TP53 signaling in WT cells. Notably, TAK-243 overcame resistance to conventional drugs and novel agents in cell-line models, including bortezomib and carfilzomib resistance, and showed activity against primary cells from relapsed/refractory myeloma patients. In addition, TAK-243 showed strong synergy with a number of antimyeloma agents, including doxorubicin, melphalan, and panobinostat as measured by low combination indices. Finally, TAK-243 was active against a number of in vivo myeloma models in association with activation of ER stress. Taken together, the data support the conclusion that UAE inhibition could be an attractive strategy to move forward to the clinic for patients with relapsed and/or refractory multiple myeloma.

• Authors: Junling Zhuang, Fazal Shirazi, Ram Kumar Singh, Isere Kuiatse, Hua Wang, Hans C Lee, Zuzana Berkova, Allison Berger, Marc Hyer, Nibedita Chattopadhyay, Sakeena Syed, Judy Qiuju Shi, Jie Yu, Vaishali Shinde, Stephen Tirrell, Richard Julian Jones, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski
• Journal: Blood (Blood) Vol. 133 Issue 14 Pg. 1572-1584 (04 04 2019) ISSN: 1528-0020 [Electronic] United States
• PMID: 30737236 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents
• Proteasome Inhibitors
• TP53 protein, human
• Tumor Suppressor Protein p53
• Ubiquitin-Activating Enzymes

Topics

• Antineoplastic Agents (therapeutic use)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• Multiple Myeloma (drug therapy)
• Oxidative Stress (drug effects)
• Proteasome Inhibitors (pharmacology)
• Salvage Therapy (methods)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (drug effects, metabolism)
• Ubiquitin-Activating Enzymes (antagonists & inhibitors)
• Unfolded Protein Response (drug effects)