靶向PI3K/AKT/mTOR信号通路治疗急性T淋巴细胞白血病的研究进展

急性T淋巴细胞白血病(T-ALL)是来源于胸腺T细胞祖细胞的具有强侵袭性和异质性的血液系统恶性肿瘤。T-ALL约占儿童急性淋巴细胞白血病(ALL)的15%,在成人ALL中的比例约为25%。强化化疗方案的应用使儿童T-ALL患者预后显著提高,但成人及复发耐药T-ALL患者的预后仍较差。研制新型靶向药物特异性阻断T-ALL细胞内生存及耐药相关的异常激活信号通路近年来被认为是治疗成人及复发难治T-ALL患者的新策略。PI3K/AKT/mTOR通路是T-ALL细胞内异常激活信号通路中具有代表性的一条。目前靶向该通路的多种小分子抑制剂已被成功研制,并在治疗T-ALL的研究中取得良好效果。PI3K/AKT/mTOR通路相关抑制剂较传统化疗药物具有更高的特异性和更低的毒副作用,且诸多研究表明其与低剂量化疗药物或其他靶向药物联合治疗T-ALL能发挥协同效应。本综述将总结近年来在PI3K/AKT/mTOR通路与T-ALL相关领域的研究成果,并对基于靶向该通路治疗T-ALL的研究进展一并阐述。

Progress in the treatment of acute T lymphoblastic leukemia by targeting PI3K/AKT/mTOR pathway

Acute T lymphoblastic leukemia(T-ALL)is a highly invasive and heterogeneous hematological malignancy derived from thymic T cell progenitor cells.T-ALL accounts for approximately 15% of childhood acute lymphoblastic leukemia(ALL)and approximately 25% of adult ALL.The use of intensive chemotherapy regimens has significantly improved the prognosis of children with T-ALL,but the prognosis of adult and relapsed T-ALL patients remains poor.The development of novel targeted drugs specifically blocking T-ALL cell survival and drug-related abnormal activation signaling pathways has been considered as a new strategy for the treatment of adult and relapsed refractory T-ALL patients in recent years.The phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin(mTOR)pathway is a representative of the abnormal activation signaling pathways in T-ALL cells.A variety of small molecule inhibitors targeting this pathway has been successfully developed and has achieved good results in the treatment of T-ALL.PI3K/AKT/mTOR pathway-related inhibitors have higher specificity and lower toxicity than traditional chemotherapeutic drugs,and many studies have shown that they can exert synergistic effects with low-dose chemotherapeutic drugs or other targeted drugs in the treatment of T-ALL.This review will summarize recent research results in the field of PI3K/AKT/mTOR pathway and T-ALL,and elaborate the research progress of T-ALL based on targeting this pathway.