1. PAI-1 mediates acquired resistance to MET-targeted therapy in non-small cell lung cancer.
- Author
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Thu YM, Suzawa K, Tomida S, Ochi K, Tsudaka S, Takatsu F, Date K, Matsuda N, Iwata K, Nakata K, Shien K, Yamamoto H, Okazaki M, Sugimoto S, and Toyooka S
- Subjects
- Humans, Cell Line, Tumor, Epithelial-Mesenchymal Transition drug effects, Gene Expression Regulation, Neoplastic drug effects, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, 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, Crizotinib pharmacology, Crizotinib therapeutic use, Drug Resistance, Neoplasm genetics, Drug Resistance, Neoplasm drug effects, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms pathology, Plasminogen Activator Inhibitor 1 metabolism, Plasminogen Activator Inhibitor 1 genetics, Proto-Oncogene Proteins c-met metabolism, Proto-Oncogene Proteins c-met genetics, Proto-Oncogene Proteins c-met antagonists & inhibitors
- Abstract
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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Shinichi Toyooka received research funding from Eli Lilly Japan, Taiho (Japan) and Chugai (Japan), and lecture fees from Chugai. All other authors have declared that no competing interests exist., (Copyright: © 2024 Thu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
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