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

• 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
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: PAI-1 / EGFR-TKI / 耐性化 / EMT / EGFR遺伝子変異 / 肺癌 / 幹細胞 / 化学療法

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.

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。

Research Products

• [Journal Article] Clinical significance of BIM deletion polymorphism in chemoradiotherapy for non-small cell lung cancer. (2021)
  • Author(s): Wakabayashi Y, Masuda T, Fujitaka K, Nakashima T, Okumoto J, Shimoji K, Nishimura Y, Yamaguchi K, Sakamoto S, Horimasu Y, Miyamoto S, Iwamoto H, Ohshimo S, Hamada H, Hattori N.
  • Journal Title: Cancer Sci. Volume: 112 Issue: 1 Pages: 369-379
  • DOI: 10.1111/cas.14711
  • Peer Reviewed / Open Access
• [Journal Article] Autoantibody Positivity Is a Risk Factor for Chemotherapy-induced Exacerbation of Interstitial Pneumonia in Lung Cancer. (2021)
  • Author(s): Ito N, Masuda T, Nakashima T, Nakao S, Yamaguchi K, Sakamoto S, Horimasu Y, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Hattori N.
  • Journal Title: Anticancer Res. Volume: 41 Issue: 3 Pages: 1497-1506
  • DOI: 10.21873/anticanres.14908
  • Peer Reviewed
• [Journal Article] Association of Preexisting Interstitial Lung Abnormalities With Immune Checkpoint Inhibitor-Induced Interstitial Lung Disease Among Patients With Nonlung Cancers. (2020)
  • Author(s): Shimoji K, Masuda T, Yamaguchi K, Sakamoto S, Horimasu Y, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Takeno S, Hide M, Teishima J, Ohdan H, Hattori N.
  • Journal Title: JAMA Netw Open. Volume: 3 Issue: 11 Pages: e2022906-e2022906
  • DOI: 10.1001/jamanetworkopen.2020.22906
  • Peer Reviewed / Open Access
• [Journal Article] Albumin-globulin ratio is a predictive biomarker of antitumor effect of anti-PD-1 antibody in patients with non-small cell lung cancer. (2019)
  • Author(s): Nakanishi Y, Masuda T, Yamaguchi K, Sakamoto S, Horimasu Y, Mimae T, Nakashima T, Miyamoto S, Tsutani Y, Iwamoto H, Fujitaka K, Miyata Y, Hamada H, Okada M, Hattori N.
  • Journal Title: Int J Clin Oncol. Volume: 25 Issue: 1 Pages: 74-81
  • DOI: 10.1007/s10147-019-01539-2
  • Peer Reviewed / Open Access
• [Journal Article] Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer. (2019)
  • Author(s): Nakanishi Y, Masuda T, Yamaguchi K, Sakamoto S, Horimasu Y, Nakashima T, Miyamoto S, Tsutani Y, Iwamoto H, Fujitaka K, Miyata Y, Hamada H, Okada M, Hattori N.
  • Journal Title: Respir Investig. Volume: 57 Issue: 5 Pages: 451-459
  • DOI: 10.1016/j.resinv.2019.05.002
  • Peer Reviewed
• [Journal Article] Comparison of anti-aminoacyl-tRNA synthetase antibody-related and idiopathic non-specific interstitial pneumonia. (2019)
  • Author(s): Shioya S, Masuda T, Yamaguchi K, Sakamoto S, Horimasu Y, Nakashima T, Miyamoto S, Senoo T, Iwamoto H, Ohshimo S, Fujitaka K, Hamada H, Hattori N.
  • Journal Title: Respir Med. Volume: 152 Pages: 44-50
  • DOI: 10.1016/j.rmed.2019.04.023
  • Peer Reviewed
• [Journal Article] Inhibition of PAI‐1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer‐associated fibroblasts (2019)
  • Author(s): Masuda Takeshi、Nakashima Taku、Namba Masashi、Yamaguchi Kakuhiro、Sakamoto Shinjiro、Horimasu Yasushi、Miyamoto Shintaro、Iwamoto Hiroshi、Fujitaka Kazunori、Miyata Yoshihiro、Hamada Hironobu、Okada Morihito、Hattori Noboru
  • Journal Title: Journal of Cellular and Molecular Medicine Volume: 23 Issue: 4 Pages: 2984-2994
  • DOI: 10.1111/jcmm.14205
  • Peer Reviewed / Open Access
• [Presentation] PAI-1 is involved in acquired resistance to osimertinib in EGFR mutated lung cancer thorough its association with EMT (2020)
  • Author(s): Kentaro Tokumo, Takeshi Masuda, Shinjiro Sakamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] PAI-1は上皮間葉転換を介してEGFR遺伝子変異陽性肺癌のOsimertinibに対する耐性獲得に関与する (2020)
  • Author(s): 徳毛健太郎、益田武、山口覚博、坂本信二郎、宮本真太郎、中島拓、岩本博志、藤高一慶、濱田泰伸、服部登
  • Organizer: 第61回日本肺癌学会学術総会
• [Presentation] PAI-1は上皮間葉転換を介してEGFR遺伝子変異陽性肺癌のOsimertinibに対する耐性獲得に関与する (2020)
  • Author(s): 徳毛健太郎、益田武、山口覚博、坂本信二郎、宮本真太郎、中島拓、岩本博志、藤高一慶、濱田泰伸、服部登
  • Organizer: 第24回日本がん分子標的治療学会学術集会
• [Presentation] PAI-1はEGFR遺伝子変異陽性肺腺癌のEGFRチロシンキナーゼ阻害薬に対する耐性獲得に関与する (2019)
  • Author(s): ○徳毛 健太郎、益田 武、山口 覚博、坂本 信二郎、堀益 靖、宮本 真太郎 中島 拓、岩本 博志、藤高 一慶、濱田 泰伸、服部 登
  • Organizer: 第61回日本肺癌学会学術集会
• [Presentation] PAI-1はEGFR遺伝子変異陽性肺腺癌のチロシンキナーゼ阻害薬に対する耐性獲得に関与する (2018)
  • Author(s): 徳毛 健太郎, 益田 武, 山口 覚博, 坂本 信二郎, 堀益 靖, 宮本 真太郎, 中島 拓, 岩本 博志, 藤高 一慶, 濱田 泰伸, 服部 登
  • Organizer: 第59回日本肺癌学会学術集会