TY - JOUR
T1 - RARγ activation sensitizes human myeloma cells to carfilzomib treatment through the OAS-RNase L innate immune pathway
AU - Wang, Qiang
AU - Lin, Zhijuan
AU - Wang, Zhuo
AU - Ye, Lingqun
AU - Xian, Miao
AU - Xiao, Liuling
AU - Su, Pan
AU - Bi, Enguang
AU - Huang, Yung hsing
AU - Qian, Jianfei
AU - Liu, Lintao
AU - Ma, Xingzhe
AU - Yang, Maojie
AU - Xiong, Wei
AU - Zu, Youli
AU - Pingali, Sai Ravi
AU - Xu, Bing
AU - Yi, Qing
N1 - Funding Information:
The authors thank Xian Chen and the Cancer Genomics Center at The University of Texas for RNA-seq service. This work was supported by Startup Support from Lerner Research Institute, Cleveland Clinic and Houston Methodist Research Institute, Houston Methodist Hospital, and Cancer Prevention & Research Institute of Texas (CPRIT) Recruitment of Established Investigator Award RR180044. The Cancer Genomics Center in The University of Texas was supported by CPRIT grant RP180734. The authors thank Research Core services in the Lerner Research Institute of the Cleveland Clinic and in the Houston Methodist Research Institute for their support.
Funding Information:
This work was supported by Startup Support from Lerner Research Institute, Cleveland Clinic and Houston Methodist Research Institute, Houston Methodist Hospital, and Cancer Prevention & Research Institute of Texas (CPRIT) Recruitment of Established Investigator Award RR180044.
Funding Information:
The Cancer Genomics Center in The University of Texas was supported by CPRIT grant RP180734. The authors thank Research Core services in the Lerner Research Institute of the Cleveland Clinic and in the Houston Methodist Research Institute for their support.
Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/1/6
Y1 - 2022/1/6
N2 - Proteasome inhibitors (PIs) such as bortezomib (Btz) and carfilzomib (Cfz) are highly efficacious for patients with multiple myeloma (MM). However, relapses are frequent, and acquired resistance to PI treatment emerges in most patients. Here, we performed a high-throughput screen of 1855 Food and Drug Administration (FDA)-approved drugs and identified all-trans retinoic acid (ATRA), which alone has no antimyeloma effect, as a potent drug that enhanced MM sensitivity to Cfz-induced cytotoxicity and resensitized Cfz-resistant MM cells to Cfz in vitro. ATRA activated retinoic acid receptor (RAR)γ and interferon-β response pathway, leading to upregulated expression of IRF1. IRF1 in turn initiated the transcription of OAS1, which synthesized 2-5A upon binding to double-stranded RNA (dsRNA) induced by Cfz and resulted in cellular RNA degradation by RNase L and cell death. Similar to ATRA, BMS961, a selective RARγ agonist, could also (re)sensitize MM cells to Cfz in vitro, and both ATRA and BMS961 significantly enhanced the therapeutic effects of Cfz in established MM in vivo. In support of these findings, analyses of large datasets of patients' gene profiling showed a strong and positive correlation between RARγ and OAS1 expression and patient's response to PI treatment. Thus, this study highlights the potential for RARγ agonists to sensitize and overcome MM resistance to Cfz treatment in patients.
AB - Proteasome inhibitors (PIs) such as bortezomib (Btz) and carfilzomib (Cfz) are highly efficacious for patients with multiple myeloma (MM). However, relapses are frequent, and acquired resistance to PI treatment emerges in most patients. Here, we performed a high-throughput screen of 1855 Food and Drug Administration (FDA)-approved drugs and identified all-trans retinoic acid (ATRA), which alone has no antimyeloma effect, as a potent drug that enhanced MM sensitivity to Cfz-induced cytotoxicity and resensitized Cfz-resistant MM cells to Cfz in vitro. ATRA activated retinoic acid receptor (RAR)γ and interferon-β response pathway, leading to upregulated expression of IRF1. IRF1 in turn initiated the transcription of OAS1, which synthesized 2-5A upon binding to double-stranded RNA (dsRNA) induced by Cfz and resulted in cellular RNA degradation by RNase L and cell death. Similar to ATRA, BMS961, a selective RARγ agonist, could also (re)sensitize MM cells to Cfz in vitro, and both ATRA and BMS961 significantly enhanced the therapeutic effects of Cfz in established MM in vivo. In support of these findings, analyses of large datasets of patients' gene profiling showed a strong and positive correlation between RARγ and OAS1 expression and patient's response to PI treatment. Thus, this study highlights the potential for RARγ agonists to sensitize and overcome MM resistance to Cfz treatment in patients.
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U2 - 10.1182/blood.2020009856
DO - 10.1182/blood.2020009856
M3 - Article
C2 - 34411225
SN - 0006-4971
VL - 139
SP - 59
EP - 72
JO - Blood
JF - Blood
IS - 1
ER -