Buchert M, Burns C J, Ernst M
Department of Medical Biology, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, Victoria, Australia.
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Austin Health, Heidelberg, Victoria, Australia.
Oncogene. 2016 Feb 25;35(8):939-51. doi: 10.1038/onc.2015.150. Epub 2015 May 18.
Various human malignancies are characterized by excessive activation of the Janus family of cytoplasmic tyrosine kinases (JAK) and their associated transcription factors STAT3 and STAT5. In the majority of solid tumors, this occurs in response to increased abundance of inflammatory cytokines in the tumor microenvironment prominently produced by infiltrating innate immune cells. Many of these cytokines share common receptor subunits and belong to the interleukin (IL)-6/IL-11, IL-10/IL-22 and IL-12/IL-23 families. Therapeutic inhibition of the JAK/STAT3 pathway potentially offers considerable benefit owing to the capacity of JAK/STAT3 signaling to promote cancer hallmarks in the tumor and its environment, including proliferation, survival, angiogenesis, tumor metabolism while suppressing antitumor immunity. This is further emphasized by the current successful clinical applications of JAK-specific small molecule inhibitors for the treatment of inflammatory disorders and hematopoietic malignancies. Here we review current preclinical applications for JAK inhibitors for the treatment of solid cancers in mice, with a focus on the most common malignancies emanating from oncogenic transformation of the epithelial mucosa in the stomach and colon. Emerging data with small molecule JAK-specific adenosine triphosphate-binding analogs corroborate genetic findings and suggest that interference with the JAK/STAT3 pathway may suppress the growth of the most common forms of sporadic colon cancers that arise from mutations of the APC tumor suppressor gene. Likewise inhibition of cytokine-dependent activation of the JAK/STAT3 pathway may also afford orthogonal treatment opportunities for other oncogene-addicted cancer cells that have gained drug resistance.
多种人类恶性肿瘤的特征是细胞质酪氨酸激酶（JAK）的Janus家族及其相关转录因子STAT3和STAT5过度激活。在大多数实体瘤中，这种情况的发生是对肿瘤微环境中炎性细胞因子丰度增加的反应，这些细胞因子主要由浸润的先天免疫细胞产生。这些细胞因子中的许多共享共同的受体亚基，属于白细胞介素（IL）-6/IL-11、IL-10/IL-22和IL-12/IL-23家族。JAK/STAT3信号通路能够促进肿瘤及其环境中的癌症特征，包括增殖、存活、血管生成、肿瘤代谢，同时抑制抗肿瘤免疫，因此对JAK/STAT3通路的治疗性抑制可能带来相当大的益处。JAK特异性小分子抑制剂目前在治疗炎症性疾病和血液系统恶性肿瘤方面的成功临床应用进一步强调了这一点。在这里，我们综述了JAK抑制剂在小鼠实体癌治疗中的当前临床前应用，重点关注胃和结肠上皮黏膜致癌转化产生的最常见恶性肿瘤。小分子JAK特异性三磷酸腺苷结合类似物的新数据证实了基因研究结果，并表明干扰JAK/STAT3通路可能会抑制由APC肿瘤抑制基因突变引起的最常见散发性结肠癌的生长。同样，抑制JAK/STAT3通路的细胞因子依赖性激活也可能为其他获得耐药性的癌基因成瘾癌细胞提供正交治疗机会。
