Molecular mechanisms of duplicate resistance to FLT3 inhibitors in acute myeloid leukemia

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06585
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Nihon University
• Principal Investigator: KATAYAMA Kazuhiro 日本大学, 薬学部, 教授 (40406963)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 急性骨髄性白血病 / FLT3阻害薬 / 逐次治療 / 交差耐性 / Wnt/β-cateninシグナル / 二重変異

Outline of Final Research Achievements

The aim of this study was to analyze the mechanism of cross-resistance to FLT3 inhibitors for the treatment of acute myeloid leukemia and to search for ways to overcome it. Duplicated resistant cells established by sequential treatment with two different FLT3 inhibitors were cross-resistant to all FLT3 inhibitors. Proliferation of these cells was dependent on Wnt/β-catenin signaling, and the combination of both inhibitors acts synergistically. In addition, analysis of transfected cells revealed double mutations in FLT3 that are cross-resistant to FLT3 inhibitors. These double mutations were considered to alter the shape of the entrance to the ATP-binding site of FLT3, resulting in reduced inhibitory activity of the inhibitors. Thus, we found that after sequential use of FLT3 inhibitors, cross-resistance emerges due to the bypass pathway and double mutations in FLT3.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

急性骨髄性白血病におけるFLT3阻害薬の交差耐性機構や、耐性克服に向けた戦略を発見できたことは、臨床現場でFLT3阻害薬に対する不応性や、治療後の再発を考察する一助になると期待される。急性骨髄性白血病では、分子標的薬の選択肢が少ないことや薬剤不応性・耐性などの問題があり、十分な生存率を望めないのが現状である。本研究成果に基づき治療戦略の見直しや治療薬の開発に繋がれば、急性骨髄性白血病治療の選択肢の幅が広がり、治療効果の向上に貢献できると推測される。治療効果の向上の恩恵を受けるのは急性骨髄性白血病患者であり、奏効・完治を達成できれば社会的な意義は非常に大きい。