Elucidation of HDAC inhibitor resistance mechanism in T-cell lymphoma and establishment of therapeutic strategies to overcome resistance

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17393
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Akita University
• Principal Investigator: Akihiro Kitadate 秋田大学, 医学部附属病院, 講師 (90791559)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: T細胞リンパ腫 / HDAC阻害剤 / JAK/STAT / gp130 / プロテアソーム阻害

Outline of Final Research Achievements

In HDAC inhibitor-resistant cells, we have found several gene expression changes, especially JAK/STAT pathway activation, abnormal cytokine-related signaling, and changes in the expression of anti-apoptotic genes. Phenotypic screening using drug screening was performed to clarify the vulnerability of HDAC inhibitor-resistant cells. Among them, we found marked hypersensitivity to bortezomib, a proteasome inhibitor. These findings may provide important suggestions for establishing therapeutic strategies for T-cell lymphomas that have acquired resistance to HDAC inhibitors.

Free Research Field

血液内科

Academic Significance and Societal Importance of the Research Achievements

HDAC阻害剤への耐性機序として、gp130を介したJAK/STAT経路活性化や、ヒストンアセチル化抑制などを見出した。これらの知見から、gp130阻害あるいはJAK/STAT経路の阻害、そして抑制されたヒストンアセチル化を回復させるプロテアソーム阻害など、いくつかの新たな治療標的を見出すことができた。これらの知見は、HDAC阻害剤治療後の再発難治性T細胞リンパ腫に対する新たな治療戦略構築のための重要な根拠となりうると考える。