Association between Plasminogen Activator Inhibitor-1 and Osimertinib Tolerance in EGFR-Mutated Lung Cancer via Epithelial–Mesenchymal Transition
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
Abstract
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.