Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal Transition
Most epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) cells are killed within a few days after osimertinib treatment; however, surviving cells remain detectable and are called drug-tolerant cells. Plasminogen activator inhibitor-1 (PAI-1) was reported to be involved...
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MDPI AG
2023-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/4/1092 |
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| author | Kentaro Tokumo Takeshi Masuda Taku Nakashima Masashi Namba Kakuhiro Yamaguchi Shinjiro Sakamoto Yasushi Horimasu Shintaro Miyamoto Hiroshi Iwamoto Kazunori Fujitaka Yoshihiro Miyata Morihito Okada Hironobu Hamada Noboru Hattori |
| author_facet | Kentaro Tokumo Takeshi Masuda Taku Nakashima Masashi Namba Kakuhiro Yamaguchi Shinjiro Sakamoto Yasushi Horimasu Shintaro Miyamoto Hiroshi Iwamoto Kazunori Fujitaka Yoshihiro Miyata Morihito Okada Hironobu Hamada Noboru Hattori |
| author_sort | Kentaro Tokumo |
| collection | DOAJ |
| description | Most epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) cells are killed within a few days after osimertinib treatment; however, surviving cells remain detectable and are called drug-tolerant cells. Plasminogen activator inhibitor-1 (PAI-1) was reported to be involved in chemotherapeutic or radiotherapeutic resistance. The purpose of the present study was to investigate whether PAI-1 is involved in osimertinib tolerance and whether it could be a therapeutic target for overcoming this tolerance. We showed that the PAI-1 mRNA expression levels and mesenchymal gene expression levels were significantly higher in drug-tolerant EGFR-mutated NSCLC cells than in control cells after 7 days of in vitro osimertinib treatment. Additionally, an RNA microarray analysis revealed upregulation of the integrin-induced EMT pathway in osimertinib-tolerant cells. Furthermore, we observed that PAI-1 inhibitors suppressed proliferation and the degree of epithelial–mesenchymal transition (EMT) in tolerant cells. Finally, in a subcutaneous tumor model, we showed that combining osimertinib with a PAI-1 inhibitor prevented the regrowth of tumors comprising EGFR-mutated cancer cells. The present study is the first to show PAI-1 to be involved in tolerance to osimertinib via EMT. |
| first_indexed | 2024-03-11T09:03:31Z |
| format | Article |
| id | doaj.art-ee217e80fa894890bd3ec0c8f2c84af7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:03:31Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ee217e80fa894890bd3ec0c8f2c84af72023-11-16T19:36:05ZengMDPI AGCancers2072-66942023-02-01154109210.3390/cancers15041092Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal TransitionKentaro Tokumo0Takeshi Masuda1Taku Nakashima2Masashi Namba3Kakuhiro Yamaguchi4Shinjiro Sakamoto5Yasushi Horimasu6Shintaro Miyamoto7Hiroshi Iwamoto8Kazunori Fujitaka9Yoshihiro Miyata10Morihito Okada11Hironobu Hamada12Noboru Hattori13Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Clinical Oncology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8551, JapanDepartment of Physical Analysis and Therapeutic Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanDepartment of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, JapanMost epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) cells are killed within a few days after osimertinib treatment; however, surviving cells remain detectable and are called drug-tolerant cells. Plasminogen activator inhibitor-1 (PAI-1) was reported to be involved in chemotherapeutic or radiotherapeutic resistance. The purpose of the present study was to investigate whether PAI-1 is involved in osimertinib tolerance and whether it could be a therapeutic target for overcoming this tolerance. We showed that the PAI-1 mRNA expression levels and mesenchymal gene expression levels were significantly higher in drug-tolerant EGFR-mutated NSCLC cells than in control cells after 7 days of in vitro osimertinib treatment. Additionally, an RNA microarray analysis revealed upregulation of the integrin-induced EMT pathway in osimertinib-tolerant cells. Furthermore, we observed that PAI-1 inhibitors suppressed proliferation and the degree of epithelial–mesenchymal transition (EMT) in tolerant cells. Finally, in a subcutaneous tumor model, we showed that combining osimertinib with a PAI-1 inhibitor prevented the regrowth of tumors comprising EGFR-mutated cancer cells. The present study is the first to show PAI-1 to be involved in tolerance to osimertinib via EMT.https://www.mdpi.com/2072-6694/15/4/1092epidermal growth factor receptorplasminogen activator inhibitor-1drug-tolerant cellsnon-small-cell lung cancerepithelial–mesenchymal transition |
| spellingShingle | Kentaro Tokumo Takeshi Masuda Taku Nakashima Masashi Namba Kakuhiro Yamaguchi Shinjiro Sakamoto Yasushi Horimasu Shintaro Miyamoto Hiroshi Iwamoto Kazunori Fujitaka Yoshihiro Miyata Morihito Okada Hironobu Hamada Noboru Hattori Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal Transition Cancers epidermal growth factor receptor plasminogen activator inhibitor-1 drug-tolerant cells non-small-cell lung cancer epithelial–mesenchymal transition |
| title | Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal Transition |
| title_full | Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal Transition |
| title_fullStr | Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal Transition |
| title_full_unstemmed | Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal Transition |
| title_short | Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal Transition |
| title_sort | association between plasminogen activator inhibitor 1 and osimertinib tolerance in egfr mutated lung cancer via epithelial mesenchymal transition |
| topic | epidermal growth factor receptor plasminogen activator inhibitor-1 drug-tolerant cells non-small-cell lung cancer epithelial–mesenchymal transition |
| url | https://www.mdpi.com/2072-6694/15/4/1092 |
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