靶向酪氨酸激酶的治疗在骨髓增殖性肿瘤中的应用研究进展

摘要

酪氨酸激酶在细胞增殖、分化及生存和凋亡等重要生命活动中起着关键作用,它们的异常与肿瘤的发生密切相关.随着酪氨酸激酶及其信号通路中的组成元件的异常在血液系统恶性疾病中不断被发现,对于酪氨酸激酶抑制剂在血液系统恶性疾病治疗中的应用越来越受关注.慢性髓系白血病治疗因BCR/ABL酪氨酸激酶抑制剂甲磺酸伊马替尼的出现而有了革命性的进展,但因耐药、耐受性及其他伴有酪氨酸激酶异常的血液系统恶性疾病的需要,它不断研发出许多新型的酪氨酸激酶抑制剂.应用甲磺酸伊马替尼的适应症现在也逐渐被扩大,包括伴有PDGFRA,PDGFRB或FGFR1嗜酸性细胞相关的髓系钟瘤,伴有c-Kit突变的胃间质瘤等.近来,JAK2激酶抑制剂也逐渐进入临床试验用于伴有JAK2 V617F突变的真性红细胞增多症、原发性骨髓纤维化、原发性血小板增多症.本文将时于酪氨酸激酶异常在骨髓增殖性肿瘤的特点,以及靶向酪氨酸激酶治疗的应用做一综述.%As well as playing vital roles in main cellular processes,such as abnomal proliferation,differentiation,survival,apoptosis,and a lot of tyrosine ldnases(TK)are involved in oncogenesis.TK or components of their signal pathways have been found abnormal in many hematological malignancies.Therefore,tyrosine kinase inhibitors(TKI)have been provided a great deal of enthusiasm for development of therapy in myeloproliferative neoplasms(MPN).Representatively,the treatment of chronic myelogenous leukemia(CML)was revolutionary for the design of imatinib mesylate(IM),which is a BCR/ABL TKI.Subsequently,because of need for the resistance or intolerance,novel agents are being explored and imatinib has now been extended to eosinophilia-associated myeloid neoplasms with PDGFRA,PDGFRB or FGFR1 gene mutations.Recently,JAK2 inhibitor drugs are currently being tested in clinical trials.Here,the current review mainly focuses on the role of TK in classic MPN including CML,polycythemia vera(PV),primary myelofibrosis(PMF),essential thrombocythemia(ET),and advances of targeting these abnormalities with small molecule inhibitors.