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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]

Osimertinib is the standard treatment for non‐small cell lung cancer (NSCLC) with an active epidermal growth factor receptor (EGFR) mutation and a T790M mutation—present in cases of acquired resistance. However, there have been no reports on the efficacy of osimertinib in patients with EGFR G719S and de novo T790M mutations. Here, we present the case of a 71‐year‐old woman who received first‐line osimertinib for lung adenocarcinoma with G719S and de novo T790M mutations. A partial response was observed after osimertinib initiation; however, the disease progressed 5 months after. Next‐generation sequencing using a rebiopsy sample from the brain metastases revealed no newly acquired resistance mutations, including EGFR C797S. From experience, the efficacy of osimertinib in NSCLC with G719S and T790M compound mutations may be poor. Therefore, optimal treatment for these cases should be determined. [ABSTRACT FROM AUTHOR]