Tyrosine kinase activations induced by HDAC inhibitors and their application to the novel treatment of CTCL

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08777
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Kagoshima University
• Principal Investigator: Fujii Kazuyasu 鹿児島大学, 医歯学域鹿児島大学病院, 講師 (70452571)
• Co-Investigator(Kenkyū-buntansha): 近藤 格 国立研究開発法人国立がん研究センター, 研究所, 分野長 (30284061)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: HDAC阻害剤 / 皮膚T細胞リンパ腫 / キノーム解析 / Src

Outline of Final Research Achievements

HDAC inhibitors (HDACis) are used to treat patients with cutaneous T-cell lymphoma (CTCL), but they show limited efficacy. Hence, combination therapies should be explored to enhance the effectiveness of HDACis. To identify novel therapeutic targets, we performed a global kinome profiling assay of three CTCL cell lines with three HDACis. Principal component analysis revealed that kinome expression patterns were mainly related to the cell origin and were not affected by the drugs. A small number of kinases were commonly activated by the HDACis. Most identified kinases were Src-associated molecules. Phosphorylated Src was not observed in any untreated cell lines, whereas Src phosphorylation was detected in two of the three cell lines after HDACi treatment. Ponatinib, a Src inhibitor, significantly enhanced romidepsin-induced apoptosis. In conclusion, the Src pathway is a possible target for combination therapy involving HDACis for CTCL.

Free Research Field

皮膚腫瘍学

Academic Significance and Societal Importance of the Research Achievements

HDAC阻害剤は皮膚T細胞リンパ腫の治療薬として使われているが、効果に限界があることが分かっており、効果を増強するための併用療法の開発が試みられているが、現時点で確立された併用療法はない。本研究ではHDAC阻害剤によりチロシンキナーゼと呼ばれる細胞内分子群の活性がどのように変化するかを解析し、Src経路と呼ばれる特定の分子群の活性が亢進していることを明らかにした。さらにSrc経路の阻害剤でHDAC阻害剤の抗腫瘍効果が増強することも明らかにした。本研究により将来的な皮膚T細胞リンパ腫の新たな治療法の確立が期待できる。