The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is an active mediator of cytokine signaling in the pathogenesis of solid and hematologic malignancies. The seven-member STAT family is composed of latent cytoplasmic transcription factors that are activated by phosphorylation intertwined in a network with activation that ultimately leads to cell proliferation. An activated kinase enzyme phosphorylates one STAT factor or more, which shuttle to the nucleus to regulate gene expression, promoting cell survival. Somatic STAT3 mutations have been recently reported in large granular lymphocytic leukemia, aplastic anemia, and myelodysplastic syndrome. Furthermore, the relationship between BCL6 and STAT3 in diffuse large B-cell lymphomas, particularly on the activated B-cell subtype, needs to be further explored. The search for therapeutic STAT3 inhibitors that abrogate the JAK/STAT pathway is currently under way. Targeting the STAT pathway, which seems to be critical in tumorigenesis, is promising for multiple malignancies including lymphoma and leukemia. In this paper, we review mechanisms of action, failures, and successes of STAT3 inhibitors.
摘要
Janus 激酶(JAK) 及信号转导及转录激活蛋白 (STAT) 通路在恶性实体肿瘤和恶性血液病的发病过程中，对细胞因子信号传递发挥着积极的介导作用。 包含七个成员的 STAT 家族由可磷酸化激活的潜伏胞浆转录因子组成，它们缠结在一个活化的网路之中，该活化的网络最终可以导致细胞增殖。 激活后的激酶可以磷酸化一个或多个 STAT 因子，使其穿梭至细胞核内调节基因表达，从而促进细胞存活。近期曾有报告称，在大颗粒淋巴细胞白血病、再生障碍性贫血和骨髓增生异常综合征中发现了体细胞 STAT3 突变。此外，BCL6 和 STAT3 在弥漫性大 B 细胞淋巴瘤中的相互关系，特别是对活化型 B 细胞亚型的影响，仍待进一步研究。针对 JAK/STAT 通路的治疗性 STAT3 抑制剂目前正处于研发之中。靶向抑制对肿瘤发生似乎具有重要作用的 STAT 通路有望成为多种恶性肿瘤的治疗手段，包括淋巴瘤和白血病。在本文中，我们回顾总结了 STAT3 抑制剂的作用机制和成败历史。The Oncologist 2014;19:536–544
Keywords: IL6; JAK; Leukemia; Lymphoma; Phase I; STAT.