Involvement of PAI-1 in maintaining the characteristic of cancer stem cells; development of treatment to cure advanced lung cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15952
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Hiroshima University
• Principal Investigator: Masuda Takeshi 広島大学, 病院(医), 助教 (80747890)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: PAI-1 / EGFR-TKI / 耐性化 / EMT

Outline of Final Research Achievements

We showed that Plasminogen activator inhibitor-1 (PAI-1) expression level was higher in tumors that acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors than in those before treatment in patients with EGFR gene mutated lung adenocarcinoma. In addition, we revealed that PAI-1 was associated with the development of acquired resistance to Osimertinib using EGFR-mutated lung cancer cells. Furthermore, it was observed that PAI-1 participate in the development of acquired resistance to Osimertinib via integrin and extracellular matrix interaction-induced epithelial-mesenchymal transition pathway. In the mouse subcutaneous tumor model, the PAI-1 expression level in tumors that acquired resistance to Osimertinib was increased compared to those before treatment. In addition, we showed that PAI-1 inhibitor and Osimertinib administration suppressed tumor resistance thereby limiting tumor regrowth.

Free Research Field

肺癌

Academic Significance and Societal Importance of the Research Achievements

肺癌の85％を占める非小細胞癌に対する薬物療法は進歩を続け、その治療成績は向上している。その中で、オシメルチニブはEGFR遺伝子変異陽性非小細胞肺癌患者に対する標準治療薬であり、本薬剤は約70%の症例において奏効することが示されている。しかし一方で、完全寛解には至る症例は非常に少なく、大部分の症例は癌細胞がオシメルチニブに対する耐性を獲得する。よって、この耐性機序を克服する治療方法の開発が求められている。本研究では、PAI-1阻害剤がオシメルチニブに対する耐性克服のための有望な治療薬となることが示されたことに大きな意義があるものと考えられる。