1. Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal Transition.
- Author
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Tokumo, Kentaro, Masuda, Takeshi, Nakashima, Taku, Namba, Masashi, Yamaguchi, Kakuhiro, Sakamoto, Shinjiro, Horimasu, Yasushi, Miyamoto, Shintaro, Iwamoto, Hiroshi, Fujitaka, Kazunori, Miyata, Yoshihiro, Okada, Morihito, Hamada, Hironobu, and Hattori, Noboru
- Subjects
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LUNG cancer & genetics , *LUNG cancer , *IN vitro studies , *GENETIC mutation , *DRUG tolerance , *CELL culture , *EPIDERMAL growth factor receptors , *ANIMAL experimentation , *PROTEIN-tyrosine kinase inhibitors , *EPITHELIAL-mesenchymal transition , *GENE expression , *MESSENGER RNA , *HISTOLOGICAL techniques , *RESEARCH funding , *BLOOD coagulation factors , *CELL lines , *POLYMERASE chain reaction , *MICE , *RNA probes , *PHARMACODYNAMICS - Abstract
Simple Summary: Osimertinib is widely employed in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Most EGFR-mutated NSCLC cells are killed within a few days after osimertinib treatment; however, surviving cells remain detectable and are called drug-tolerant cells. Avoiding drug tolerance would maintain the long-term efficacy of osimertinib. We showed that the expression of PAI-1 and mesenchymal genes in EGFR-mutated cancer cell lines was upregulated after developing tolerance to EGFR-TKIs in vitro. In addition, PAI-1 inhibition limited the proliferation and mesenchymal gene expression of EGFR-TKI-tolerant cells. These results indicate that PAI-1 is involved in drug tolerance to EGFR-TKIs via epithelial–mesenchymal transition. Furthermore, we demonstrated that the combination of osimertinib with a PAI-1 inhibitor prevented the regrowth of osimertinib-treated tumors composed of EGFR-mutated cancer cells in in vivo experiments. Based on these observations, PAI-1 may prove to be a potential therapeutic target for overcoming tolerance to osimertinib. 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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