Development of therapeutic strategies targeting molecular mechanisms underlying the therapy resistance endowed by activated tyrosine kinase mutants in hematological malignancies

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Miura Osamu 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10209710)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 血液腫瘍学 / 分子標的療法 / チロシンキナーゼ / FLT3-ITD / JAK2-V617F / プロテアソーム阻害薬 / USP9X / RSK

Outline of Final Research Achievements

We have aimed to gain new insights to develop novel molecular targeted therapies against hematopoietic malignancies with constitutively activated aberrant tyrosine kinase mutants, which play important roles not only in pathogenesis but also in acquisition of therapy resistance. We have elucidated the molecular mechanisms underlying resistance of FLT3-ITD acute myeloid leukemia to proteasome inhibitors and also have found that USP9X and RSK1 represent particularly effective targets for therapies against this disease with poor prognosis especially when the STAT5/Pim/mTORC1/Mcl-1 pathway is targeted in combination. Furthermore, USP9X was found to be a promising therapeutic target also for JAK2-V617F-positive myeloproliferative neoplasms, with its inhibitor as well as BH3 mimetics showing prominent effects particularly in ruxolitinib persistent cells.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

本研究は種々の造血器腫瘍で高頻度に認められる代表的かつ重要な恒常的活性化型チロシンキナーゼ変異体に関して、それぞれの疾患の発症や進展のみでなく治療抵抗性獲得にも寄与する細胞内シグナル伝達機構を新たな因子や伝達経路の関与を含めて詳細に明らかにするもので、細胞生物学や腫瘍治療学研究の発展に寄与する学術的意義を有するものである。また、臨床開発中や臨床応用がなされている分子標的薬等を用いた検討により得られた成果は、難治性造血器腫瘍の新規統合的分子標的療法開発へ向けて臨床的にも直接的に貢献しうる社会的意義を有する。