不可逆 FLT3 抑制剂 FF-10101 对多种 FLT3 抑制剂耐药机制有效。
The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms.
机构信息
Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
出版信息
Mol Cancer Ther. 2022 May 4;21(5):844-854. doi: 10.1158/1535-7163.MCT-21-0317.
Abstract
Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance-causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.
摘要
小分子 FLT3 抑制剂经过多年的发展，最近改善了 FLT3 突变型急性髓系白血病（AML）患者的临床结局，但耐药性仍然是一个重要的临床问题。FF-10101 是第一个不可逆的、共价的 FLT3 抑制剂，先前已显示对 FLT3 酪氨酸激酶抑制剂耐药性引起的 FLT3 F691L 和 D835 突变具有活性。我们报告称，FF-10101 对与其他 FLT3 抑制剂耐药相关的临床鉴定的 FLT3 突变的扩展面板也具有活性。我们还证明，FF-10101 可以潜在地解决与存在于骨髓微环境中的生长因子相关的耐药机制，但易受 C695 突变的影响，C695 是共价结合 FLT3 所需的氨基酸。这些数据表明，FF-10101 具有有利的耐药谱，当用于 FLT3 突变型 AML 患者时，可能有助于提高单药疗效。
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