Sonkin Dmitriy, Palmer Michael, Rong Xianhui, Horrigan Kim, Regnier Catherine H, Fanton Christie, Holash Jocelyn, Pinzon-Ortiz Maria, Squires Matthew, Sirulnik Andres, Radimerski Thomas, Schlegel Robert, Morrissey Michael, Cao Z Alexander
Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
Novartis Oncology Translational Medicine, Cambridge, MA, USA.
Cancer Biomark. 2015;15(1):79-87. doi: 10.3233/CBM-140434.
The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Dysregulated JAK-STAT signaling has been implicated in the pathogenesis of multiple human malignancies.
Given this pivotal role of JAK-STAT dysregulation, it is important to identify patients with an overactive JAK-STAT pathway for possible treatment with JAK inhibitors.
We developed a gene signature assay to detect overactive JAK-STAT signaling. The cancer cell line encyclopedia and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes.
Four target genes were identified (PIM1, CISH, SOCS2, and ID1), the expression of which correlated significantly with pSTAT5 status in 40 hematologic tumor cell lines. In pSTAT5-positive models, the expression of the gene signature genes decreased following ruxolitinib treatment, which corresponded to pSTAT5 downmodulation. In pSTAT5-negative cell lines, neither pSTAT5 modulation nor a change in signature gene expression was observed following ruxolitinib treatment.
The gene signature can potentially be used to stratify or enrich for patient populations with activated JAK-STAT5 signaling that might benefit from treatments targeting JAK-STAT signaling. Furthermore, the 4-gene signature is a predictor of the pharmacodynamic effects of ruxolitinib.
JAK-STAT信号通路是多种细胞因子和生长因子受体下游的重要信号通路。JAK-STAT信号失调与多种人类恶性肿瘤的发病机制有关。
鉴于JAK-STAT失调的这一关键作用，识别JAK-STAT通路过度活跃的患者以便用JAK抑制剂进行可能的治疗很重要。
我们开发了一种基因特征检测方法来检测过度活跃的JAK-STAT信号。利用癌细胞系百科全书和相关基因表达数据将STAT5的激活状态与一组STAT5靶基因的诱导相关联。
鉴定出四个靶基因（PIM1、CISH、SOCS2和ID1），其表达与40种血液肿瘤细胞系中的pSTAT5状态显著相关。在pSTAT5阳性模型中，鲁索替尼治疗后基因特征基因的表达下降，这与pSTAT5下调相对应。在pSTAT5阴性细胞系中，鲁索替尼治疗后未观察到pSTAT5调节或特征基因表达的变化。
该基因特征可能用于对可能从靶向JAK-STAT信号的治疗中获益的JAK-STAT5信号激活的患者群体进行分层或富集。此外，四基因特征是鲁索替尼药效学效应的预测指标。
