Strategy for development of inhibitors targeting PRMT5 for promoting synthetic lethality

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07128
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Saitama Medical University (2022-2023); University of Miyazaki (2021)
• Principal Investigator: Ichikawa Tomonaga 埼玉医科大学, 医学部, 講師 (80586230)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: PRMT5 / NDRG2 / HSP90 / ATL / がん

Outline of Final Research Achievements

A novel tumor suppressor N-Myc downstream-regulated gene 2 (NDRG2) is frequently downregulated in many types of tumors, including adult T-cell leukemia/lymphoma (ATL). The loss of NDRG2 expression is involved in aberrant activation of signal transduction pathways through continuous phosphorylation of several signaling molecules, leading to tumor progression. Furthermore, we identified cytoplasmic and hyperphosphorylated protein arginine methyltransferase 5 (PRMT5) associates with abnormal protein arginine methylation in NDRG2low ATL. We found that the suppression of PRMT5, and binding partner expression or the inhibition of enzymatic activity remarkably induces synthetic lethality followed by cell death in NDRG2low ATL. Therefore, the purpose of this study is to analyze the mechanism of synthetic lethality and to lead to a feasible and effective strategy for development of specific inhibitors that targets PRMT5 enzymatic activity for promoting synthetic lethality in NDRG2low cancers.

Free Research Field

腫瘍生物学関連

Academic Significance and Societal Importance of the Research Achievements

NDRG2発現低下によってストレス応答の恒常性維持機構が破綻し、慢性炎症、異常な情報伝達系および翻訳後修飾の亢進が惹起され、腫瘍発症進展、予後不良、薬剤抵抗性および生存率低下に関与している。そのため、NDRG2欠損がん細胞で特異的に「合成致死」を引き起こすPRMT5阻害を標的とした阻害剤はがんに特異的に効果を発揮し、NDRG2発現が保たれる正常細胞では影響を回避できる可能性が高い。また、検索しようとしている阻害剤は細胞質でのPRMT5阻害効果であり、作用点の違う細胞表面を標的とする抗体、分子標的薬や核内を標的する阻害剤と併用することで容量の低減や副作用の軽減に繋がる可能性がある。