PAI-1 mediates acquired resistance to MET-targeted therapy in non-small cell lung cancer

• Published in: PloS one 2024-05, Vol.19 (5), p.e0300644
• Main Authors: Thu, Yin Min, Suzawa, Ken, Tomida, Shuta, Ochi, Kosuke, Tsudaka, Shimpei, Takatsu, Fumiaki, Date, Keiichi, Matsuda, Naoki, Iwata, Kazuma, Nakata, Kentaro, Shien, Kazuhiko, Yamamoto, Hiromasa, Okazaki, Mikio, Sugimoto, Seiichiro, Toyooka, Shinichi
• Format: Article
• Language: English
• Subjects: Amplification; Antibodies; Antimitotic agents; Antineoplastic agents; Biology and life sciences; c-Met protein; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Crizotinib - pharmacology; Crizotinib - therapeutic use; Drug dosages; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epithelial-Mesenchymal Transition - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Genes; Health aspects; Humans; Inhibitors; Kinases; Ligands; Lung cancer; Lung cancer, Small cell; Lung carcinoma; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; MAP kinase; Medical prognosis; Medicine and Health Sciences; MEK inhibitors; Mitogens; Non-small cell lung carcinoma; Phosphorylation; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen activator inhibitors; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Research and analysis methods; Signal transduction; Small cell lung carcinoma; Transcriptomics; Tumor cell lines; Tyrosine; Tyrosine kinase inhibitors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0300644

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.