FLT3抑制剂及逆转急性髓系白血病耐药的新型治疗策略：最新综合综述

FLT3 inhibitors and novel therapeutic strategies to reverse AML resistance: An updated comprehensive review.

作者信息

Abdel-Aziz Amal Kamal, Dokla Eman M E, Saadeldin Mona Kamal

机构信息

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt; Smart Health Initiative, Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt.

出版信息

Crit Rev Oncol Hematol. 2023 Nov;191:104139. doi: 10.1016/j.critrevonc.2023.104139. Epub 2023 Sep 15.

DOI:10.1016/j.critrevonc.2023.104139

PMID:37717880

Abstract

FMS-like tyrosine kinase 3 (FLT3) mutations occur in almost 30% of acute myeloid leukemia (AML) patients. Despite the initial clinical efficacy of FLT3 inhibitors, many treated AML patients with mutated FLT3 eventually relapse. This review critically discusses the opportunities and challenges of FLT3-targeted therapies and sheds light on their drug interactions as well as potential biomarkers. Furthermore, we focus on the molecular mechanisms underlying the resistance of FLT3 internal tandem duplication (FLT3-ITD) AMLs to FLT3 inhibitors alongside novel therapeutic strategies to reverse resistance. Notably, dynamic heterogeneous patterns of clonal selection and evolution contribute to the resistance of FLT3-ITD AMLs to FLT3 inhibitors. Ongoing preclinical research and clinical trials are actively directed towards devising rational "personalized" or "patient-tailored" combinatorial therapeutic regimens to effectively treat patients with FLT3 mutated AML.

摘要

类FMS样酪氨酸激酶3（FLT3）突变发生在近30%的急性髓系白血病（AML）患者中。尽管FLT3抑制剂具有初步的临床疗效，但许多接受治疗的FLT3突变AML患者最终仍会复发。本综述批判性地讨论了FLT3靶向治疗的机遇与挑战，阐明了它们的药物相互作用以及潜在的生物标志物。此外，我们关注FLT3内部串联重复（FLT3-ITD）AML对FLT3抑制剂耐药的分子机制以及逆转耐药的新治疗策略。值得注意的是，克隆选择和进化的动态异质性模式导致了FLT3-ITD AML对FLT3抑制剂的耐药性。正在进行的临床前研究和临床试验正积极致力于设计合理的“个性化”或“患者定制”联合治疗方案，以有效治疗FLT3突变的AML患者。