The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells
The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells
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DOI：
10.1038/leu.2011.175
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发表时间：
2011-12-01
期刊：
影响因子：
11.4
通讯作者：
Spencer, A.
中科院分区：
文献类型：
--
作者：
Monaghan, K. A.;Khong, T.;Spencer, A.
Janus激酶（JAK）参与恶性细胞利用的各种信号传导途径。在多发性骨髓瘤（MM）中，IL-6/JAK/信号转导和转录激活因子（IL-6/JAK/STAT）通路是多年来研究的焦点，IL-6在MM耐药中的作用已被确定。JAK因此成为抗MM治疗的合理药物靶点。CYT 387是一种新的口服生物可利用的JAK 1/2抑制剂，最近已被描述。CYT 387治疗MM的临床前评价表明，CYT 387能够预防IL-6诱导的STAT 3磷酸化，并大大降低IL-6和胰岛素样生长因子-1诱导的人骨髓瘤细胞系（HMCL）中AKT和细胞外信号调节激酶的磷酸化。CYT 387在6/8 HMCL中以时间和剂量依赖性方式抑制MM增殖，并且这并未通过添加外源性IL-6（3/3 HMCL）而消除。在所有检测的HMCL（3/3）中，细胞周期受到抑制，细胞聚集在G2/M期，细胞凋亡被CYT 387诱导。当与常规抗MM疗法美法仑和硼替佐米联合使用时，CYT 387在杀死HMCL方面具有协同作用。重要的是，在原代患者MM细胞（n = 6）中，CYT 387作为单一药剂也诱导了细胞凋亡，并且当与常规疗法组合时再次观察到协同作用。Leukemia（2011）25，1891-1899; doi：10.1038/leu.2011.175; 2011年7月26日在线发表
Janus kinases (JAKs) are involved in various signalling pathways exploited by malignant cells. In multiple myeloma (MM), the interleukin-6/JAK/signal transducers and activators of transcription (IL-6/JAK/STAT) pathway has been the focus of research for a number of years and IL-6 has an established role in MM drug resistance. JAKs therefore make a rational drug target for anti-MM therapy. CYT387 is a novel, orally bioavailable JAK1/2 inhibitor, which has recently been described. This preclinical evaluation of CYT387 for treatment of MM demonstrated that CYT387 was able to prevent IL-6-induced phosphorylation of STAT3 and greatly decrease IL-6- and insulin-like growth factor-1-induced phosphorylation of AKT and extracellular signal-regulated kinase in human myeloma cell lines (HMCL). CYT387 inhibited MM proliferation in a time- and dose-dependent manner in 6/8 HMCL, and this was not abrogated by the addition of exogenous IL-6 (3/3 HMCL). Cell cycling was inhibited with a G2/M accumulation of cells, and apoptosis was induced by CYT387 in all HMCL tested (3/3). CYT387 synergised in killing HMCL when used in combination with the conventional anti-MM therapies melphalan and bortezomib. Importantly, apoptosis was also induced in primary patient MM cells (n = 6) with CYT387 as a single agent, and again synergy was seen when combined with conventional therapies. Leukemia (2011) 25, 1891-1899; doi:10.1038/leu.2011.175; published online 26 July 2011