机构：[1]Department of Haematology, The Second Affiliated Hospital of Soochow University, Suzhou, China[2]Department of Cell Biology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China[3]Department of Bioinformatics, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China
Treatment failure remains a main challenge in the management of high-risk multiple myeloma (MM) even with the expanding repertoire of new drugs. Combinatorial therapy is considered an encouraging strategy that can overcome the compensatory mechanisms and undesirable off-target effects that limit the benefits of many prospective agents. Preliminary results of a current phase I trial have indicated that the new BET bromodomain inhibitor OTX015 has favorable activity and tolerability. However, OTX015 is not efficacious enough as a monotherapy. Here, we provide evidence that synergistic drug combinations with OTX015 were generally more specific to particular cellular contexts than single agent activities. In addition, pairing OTX015 with three classes of drugs dramatically enhanced the antitumor activity in mouse models of disseminated human myeloma. Our studies further underscored that the BET inhibitor OTX015 sensitized MM cells by interrupting several pathways and genes critical for MM cell proliferation and drug response, which provided the rationale for multiple myeloma therapy with OTX015 combined with conventional chemotherapeutic drugs. Thus, the context specificity of synergistic combinations not only provide profound insights into therapeutically relevant selectivity but also improve control of complex biological systems.
基金：
This research was supported by Natural Science Foundation of
Jiangsu Province China (nos. BK 20161218, BK20161223),
National Natural Science Foundation of China (nos.
81673448, 81670191), the Applied Basic Research Programs
of Suzhou City (no. SYS201546), and a Project Funded by the
Priority Academic Program Development of Jiangsu Higher
Education Institutions and the Science and Technology
Development Project of Suzhou City (no. SS201856).
语种：
外文
被引次数：
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|2 区医学
小类|2 区医学：研究与实验2 区药学
最新[2023]版：
大类|2 区医学
小类|2 区药学3 区医学：研究与实验
JCR分区：
出版当年[2016]版：
Q1MEDICINE, RESEARCH & EXPERIMENTALQ1PHARMACOLOGY & PHARMACY
最新[2023]版：
Q1PHARMACOLOGY & PHARMACYQ2MEDICINE, RESEARCH & EXPERIMENTAL
第一作者机构：[1]Department of Haematology, The Second Affiliated Hospital of Soochow University, Suzhou, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Haematology, The Second Affiliated Hospital of Soochow University, Suzhou, China[2]Department of Cell Biology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China
推荐引用方式(GB/T 7714)：
Jie Gu ,Sha Song,Huiying Han,et al.The BET Bromodomain Inhibitor OTX015 Synergizes with Targeted Agents in Multiple Myeloma[J].MOLECULAR PHARMACEUTICS.2018,15(11):5387-5396.doi:10.1021/acs.molpharmaceut.8b00880.
APA：
Jie Gu,,Sha Song,Huiying Han,Hongxia Xu,Gao Fan,...&Bingzong Li.(2018).The BET Bromodomain Inhibitor OTX015 Synergizes with Targeted Agents in Multiple Myeloma.MOLECULAR PHARMACEUTICS,15,(11)
MLA：
Jie Gu,,et al."The BET Bromodomain Inhibitor OTX015 Synergizes with Targeted Agents in Multiple Myeloma".MOLECULAR PHARMACEUTICS 15..11(2018):5387-5396
