Targeting supernumerary centrosomes clustering by CDK2 inhibition to combat lung cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22833
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Kawakami Masanori 東京大学, 医学部附属病院, 特任講師 (90438648)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: サイクリン依存性キナーゼ２ / 過剰中心体 / 多極性細胞分裂 / 肺癌

Outline of Final Research Achievements

Cancer cells are genetically unstable and often have supernumerary centrosomes. When supernumerary centrosome clustering is inhibited at mitosis, multipolar cell division is forced, triggering apoptosis in daughter cells. This pro-apoptotic pathway is called anaphase catastrophe. Anaphase catastrophe eradicates aneuploid cancer cells while relatively sparing normal diploid cells with two centrosomes. This therapeutic window discriminates between normal and neoplastic cells and can be exploited in the cancer clinic. Cyclin dependent kinase 2 inhibitors can antagonize centrosome clustering and cause anaphase catastrophe to occur in lung and other cancers. In this study, we comprehensively studied the appearance of anaphase catastrophe in lung cancer cell lines and lung cancer mouse models using CYC065, a CDK2/9 inhibitor, and showed its pre-clinical activity against lung cancer. This study helps guide future CYC065 clinical trials.

Free Research Field

肺癌

Academic Significance and Societal Importance of the Research Achievements

癌細胞では過剰中心体を高頻度に認めることは臨床的にも報告されてきたが、この過剰中心体を癌治療に利用する試みの報告は多くなく、実用臨床からは遠いのが実情である。本研究で、過剰中心体収束の阻害によるanaphase catastrophe誘導を、既に臨床試験中のCDK2阻害薬で、さらには、厳しい予後である肺癌を対象として示したことは、同アプローチによる癌治療戦略の可能性を広げ、学術的にも臨床的にも意義深いものと考えている。