TY - JOUR
T1 - Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma
AU - Zhuang, Junling
AU - Shirazi, Fazal
AU - Singh, Ram Kumar
AU - Kuiatse, Isere
AU - Wang, Hua
AU - Lee, Hans C.
AU - Berkova, Zuzana
AU - Berger, Allison
AU - Hyer, Marc
AU - Chattopadhyay, Nibedita
AU - Syed, Sakeena
AU - Shi, Judy Qiuju
AU - Yu, Jie
AU - Shinde, Vaishali
AU - Tirrell, Stephen
AU - Jones, Richard Julian
AU - Wang, Zhiqiang
AU - Eric Davis, R.
AU - Orlowski, Robert Z.
N1 - Funding Information:
J.Z. acknowledges support from the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (CAMS-2016-I2M-3-025). R.Z.O. acknowledges support received as the Florence Maude Thomas Cancer Research Professor, and support from the National Institutes of Health, National Cancer Institute (P50 CA142509, R01 CA184464, R01 CA194264, and U10 CA032102), the Leukemia & Lymphoma Society (SCOR-12206-17), the Adelson Medical Research Foundation, the Brock Family Myeloma Research Fund, and the Jean Clarke High-Risk Myeloma Research Fund. Core facilities that were key to these studies, including the Characterized Cell Line Core and the Flow Cytometry and Cellular Imaging Core, were supported by the MD Anderson Cancer Center Support Grant (National Cancer Institute P30 CA016672). Additional support came from the MD Anderson Cancer Center High-Risk Multiple Myeloma Moon Shot, the Yates Ortiz Myeloma Fund, and the Diane & John Grace Family Foundation.
Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019/4/4
Y1 - 2019/4/4
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2018-06-859686
DO - 10.1182/blood-2018-06-859686
M3 - Article
C2 - 30737236
AN - SCOPUS:85064313994
SN - 0006-4971
VL - 133
SP - 1572
EP - 1584
JO - Blood
JF - Blood
IS - 14
ER -