A study on mechanisms underlying the initial survival of tumor cells against tyrosine kinase inhibitors based on patient-derived tumor models and in vivo real-time imaging

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K23964
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Nagoya University (2020); Kyoto University (2019)
• Principal Investigator: Tsuji Takahiro 名古屋大学, 医学系研究科, 研究員 (50850046)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Keywords: ALK陽性肺癌 / 薬剤耐性 / YAP1 / 治療抵抗性 / 治療初期生存 / 生体イメージング / 転移性脳腫瘍 / 画像解析

Outline of Final Research Achievements

Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.

Free Research Field

肺癌　転移性脳腫瘍

Academic Significance and Societal Importance of the Research Achievements

肺癌の薬剤耐性の研究は盛んに行われてきたが、初期生存の研究は少なく、メカニズムは不明である。完全寛解を目指した集中的な治療法は開発されておらず、進行肺癌に対する薬物治療は、数十年前から緩和化学療法と位置づけられている。本研究は、ALK陽性肺癌の根治を目指した多剤併用療法を検討した最初の研究である。この成果をもとに薬剤開発が進めば、薬によって根治を目指した治療を開発できる可能性があり、その社会的な意義は大きい。