STAT3 mediates signalling downstream of cytokine and growth factor receptors where it acts as a transcription factor for its target genes, including oncogenes and cell survival regulating genes. STAT3 has been found to be persistently activated in many types of cancers, primarily through its tyrosine phosphorylation (Y705). Here, we show that constitutive STAT3 activation protects cells from cytotoxic drug responses of several drug classes. To find novel and potentially targetable STAT3 regulators we performed a kinase and phosphatase siRNA screen with cells expressing either a hyperactive STAT3 mutant or IL6-induced wild type STAT3. The screen identified cell division cycle 7-related protein kinase (CDC7), casein kinase 2, alpha 1 (CSNK2), discoidin domain-containing receptor 2 (DDR2), cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 4-kinase 2-alpha (PI4KII), C-terminal Src kinase (CSK) and receptor-type tyrosine-protein phosphatase H (PTPRH) as potential STAT3 regulators. Using small molecule inhibitors targeting these proteins, we confirmed dose and time dependent inhibition of STAT3-mediated transcription, suggesting that inhibition of these kinases may provide strategies for dampening STAT3 activity in cancers.

STAT3介导细胞因子和生长因子受体下游的信号传导，在其中它充当其靶基因（包括癌基因和细胞存活调节基因）的转录因子。已经发现STAT3主要通过酪氨酸磷酸化（Y705）在许多类型的癌症中被持续激活。在这里，我们表明本构STAT3激活保护细胞免受几种药物类别的细胞毒性药物反应。为了找到新颖且潜在可靶向的STAT3调节剂，我们对表达高活性STAT3突变体或IL6诱导的野生型STAT3的细胞进行了激酶和磷酸酶siRNA筛选。该筛查确定了与细胞分裂周期7​​相关的蛋白激酶（CDC7），酪蛋白激酶2，α1（CSNK2），含盘状蛋白结构域的受体2（DDR2），细胞周期蛋白依赖性激酶8（CDK8），磷脂酰肌醇4激酶2-alpha（PI4KII），C端Src激酶（CSK）和受体型酪氨酸蛋白磷酸酶H（PTPRH）作为潜在的STAT3调节剂。使用针对这些蛋白质的小分子抑制剂，我们证实了STAT3介导的转录的剂量和时间依赖性抑制，表明对这些激酶的抑制可能提供抑制癌症中STAT3活性的策略。