Abstract:
ABSTRACTSmall molecule therapy is a critical component of targeted anticancer treatment, with tyrosine kinase inhibitors (TKIs) being the first compounds to treat the clonal Chronic Myelogenous Leukaemia (CML) translocation t (9;22) (q34; q11) effectively since 2001. TKIs, such as imatinib, have improved the 10-year survival rate of CML patients to 80%. They bind the BCR::ABL1 kinase and inhibit downstream signaling pathways. However, therapy failure may be seen in 20-25% of CML patients due to intolerance or inadequacy related to BCR::ABL1 dependent or independent mechanisms. This review aimed to summarize current treatment options involving TKIs, resistance mechanisms and the prospective approaches to overcome TKI resistance. We highlight BCR::ABL1-dependent mechanisms of TKI resistance by reviewing clinically-documented BCR::ABL1 mutations and their consequences for TKI binding. In addition, we summarize BCR::ABL1 independent pathways, including the relevance of drug efflux, dysregulation of microRNA, and the involvement of alternative signaling pathways. We also discuss future approaches, such as gene-editing techniques in the context of CML, as potential therapeutic strategies.
摘要:
摘要小分子治疗是靶向抗癌治疗的重要组成部分,酪氨酸激酶抑制剂(TKIs)是自2001年以来有效治疗克隆性慢性粒细胞白血病(CML)易位t(9;22)(q34;q11)的第一个化合物。TKIs,比如伊马替尼,将CML患者的10年生存率提高到80%。它们结合BCR::ABL1激酶并抑制下游信号通路。然而,由于BCR::ABL1依赖或独立机制相关的不耐受或不充分,20-25%的CML患者可能出现治疗失败.这篇综述旨在总结目前涉及TKIs的治疗方案,抗性机制和克服TKI抗性的前瞻性方法。我们通过回顾临床记录的BCR::ABL1突变及其对TKI结合的影响,重点介绍了TKI耐药的BCR::ABL1依赖性机制。此外,我们总结BCR::ABL1独立途径,包括药物外排的相关性,microRNA的失调,以及替代信号通路的参与。我们还讨论了未来的方法,比如CML背景下的基因编辑技术,作为潜在的治疗策略。