The effects of Overexpression of PLK1, a poorer prognostic factor in many types of malignancies, on DNA repair and a sensitivity to PARP inhibition

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K16316
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Sakura Anna 聖マリアンナ医科大学, 医学研究科, 研究技術員 (80626698)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 乳癌

Outline of Final Research Achievements

The overexpression of PLK1 has been found to be associated with poor clinical outcomes in many types of cancer, making it an attractive target for therapy. While recent studies have shown that PLK1 is involved in homologous recombination (HR), it is not clear how its overexpression affects HR. Analysis of The Cancer Genome Atlas dataset in combination with HR deficiency (HRD) score has revealed that overexpression of PLK1 suppresses HR. This finding is also supported by analysis of the Cancer Cell Line Encyclopedia dataset. Additionally, overexpression of PLK1 has been found to attenuate RAD51 focus formation in U2OS cells. Cells with HR defects are more sensitive to PARP inhibitors. Analysis of the CCLE dataset has shown a positive correlation between PLK1 expression levels and sensitivity to PARP inhibitors. Overexpression of PLK1 has been linked to increased sensitivity to PARP inhibition in U2OS cells. This has also been observed in ex-vivo analysis of ovarian cancer specimens.

Free Research Field

腫瘍学

Academic Significance and Societal Importance of the Research Achievements

近年の報告でPLK1が相同組換え修復に関わることが明らかになりつつあるが、PLK1過剰発現が相同組換え修復に及ぼす影響は不明であった。本研究にてPLK1過剰発現が相同組換え修復を抑制することが明らかになった。これによりPLK1の相同組換え修復への関わりの理解が深まることが予想される。またPLK1過剰発現は多くの癌でみられ、予後不良と関連があるが、PLK1過剰発現癌に対する効果的治療方法は確立されていない。本研究により予後不良であるPLK1過剰発現癌に対し、PARP阻害薬という合成致死に基づく理論上副作用のない理想的な抗癌剤を用いた薬剤が効果的治療方法となりうることを示した。