Targeting supernumerary centrosomes clustering by CDK2 inhibition to combat lung cancer

• 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• 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 / サイクリン依存性キナーゼ2 / 染色体不安定性

Outline of Research at the Start

肺癌細胞でサイクリン依存性キナーゼ2(CDK2)の阻害により、癌細胞のhallmarkの一つである過剰中心体の細胞分裂時の二極への収束が阻害され、細胞が多極性分裂を余儀なくされアポトーシスに至ることが報告されている。通常、正常細胞には過剰中心体は存在しないので、anaphase catastrophe誘導は癌細胞に特異的な治療戦略として期待できる。本研究ではCDK2選択性の高い次世代CDK2阻害薬であるCYC065と、種々の肺癌細胞株、肺癌マウスモデルを用い、CDK2阻害剤による過剰中心体収束抑制の機構を新たな癌治療戦略として確立することを目指す。

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.

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。

Research Products

• [Journal Article] A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers (2021)
  • Author(s): Kawakami M, Mustachio LM, Chen Y, Chen Z, Liu X, Wei CH, Roszik J, Kittai AS, Danilov AV, Zhang X, Fang B, Wang J, Heymach JV, Tyutyunyk-Massey L, Freemantle SJ, Kurie JM, Liu X, Dmitrovsky E
  • Journal Title: Mol Cancer Ther Volume: 20 Issue: 3 Pages: 477-489
  • DOI: 10.1158/1535-7163.mct-19-0987
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TRIGGERING ANAPHASE CATASTROPHE TO COMBAT ANEUPLOID CANCERS (2020)
  • Author(s): Dmitrovsky E, Kawakami M, Liu X, Freemantle SJ, Kurie JM
  • Journal Title: Trans Am Clin Climatol Assoc Volume: 131 Pages: 82-94
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Novel targets to treat lung cancer (2021)
  • Author(s): Kawakami M
  • Organizer: The 25th Congress of the Asian Pacific Society of Respirology
  • Int'l Joint Research / Invited
• [Presentation] Inducing Anaphase Catastrophe by CDK2 inhibitors to combat lung cancer (2020)
  • Author(s): Kawakami M, Mustachio LM, Chen Y, Chen Z, Roszik J, Heymach JV, Kurie JM, Liu x, Dmitrovsky E
  • Organizer: 第60回日本呼吸器学会学術講演会