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

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 and Robert Z. Orlowski

Key points

  • Ubiquitin-activating enzyme inhibition with TAK-243 induces an endoplasmic reticulum stress response and apoptosis in myeloma models.

  • TAK-243 overcomes drug resistance, and shows activity against primary and in vivo models, supporting its translation to the clinic.

Abstract

Three proteasome inhibitors have garnered regulatory approvals in various multiple myeloma settings but drug resistance is an emerging challenge, and this has prompted interest in blocking upstream components of the ubiquitin-proteasome pathway. One such attractive target is the E1 ubiquitin activating enzyme (UAE), and 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, MCL-1, and c-MYC, and activation of the ATF6, IRE-1, and PERK arms of the endoplasmic reticulum stress response pathway, as well as oxidative stress. UAE inhibition showed comparable activity against otherwise isogenic cell lines with wild-type or deleted p53 despite induction of TP53 signaling in wild-type 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 anti-myeloma 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 endoplasmic reticulum 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.

  • Submitted June 29, 2018.
  • Accepted January 24, 2019.