Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07740 Jena, Germany.
Innere Medizin C, Universitätsmedizin Greifswald, Sauerbruchstrasse, 17475 Greifswald, Germany.
Cells. 2020 Nov 17;9(11):2493. doi: 10.3390/cells9112493.
Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of next-generation FLT3-inhibitors, such as midostaurin and gilteritinib, we still observe primary and secondary resistance to TKI both in monotherapy and in combination with chemotherapy. Moreover, remissions are frequently short-lived even in the presence of continuous treatment with next-generation FLT3 inhibitors. In this comprehensive review, we focus on molecular mechanisms underlying the development of resistance to relevant FLT3 inhibitors and elucidate how this knowledge might help to develop new concepts for improving the response to FLT3-inhibitors and reducing the development of resistance in AML. Tailored treatment approaches that address additional molecular targets beyond FLT3 could overcome resistance and facilitate molecular responses in AML.
尽管新型 FLT3 靶向酪氨酸激酶抑制剂（TKI）的发展，治疗 FMS 样酪氨酸激酶 3（FLT3）-内部串联重复（ITD）阳性急性髓系白血病（AML）仍然是一个挑战；即使进行异基因造血干细胞移植后，复发率仍然很高。在下一代 FLT3 抑制剂（如米哚妥林和吉特替尼）时代，我们在单药治疗和联合化疗中均观察到对 TKI 的原发性和继发性耐药。此外，即使持续使用下一代 FLT3 抑制剂治疗，缓解也常常是短暂的。在这篇全面的综述中，我们重点关注导致对相关 FLT3 抑制剂产生耐药性的分子机制，并阐明这些知识如何帮助开发新的概念，以提高对 FLT3 抑制剂的反应，并降低 AML 中耐药性的发展。针对 FLT3 以外的其他分子靶点的定制治疗方法可以克服耐药性，并促进 AML 中的分子反应。
