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Cancer Research and Treatment > Accepted Articles
doi: https://doi.org/10.4143/crt.2018.052    [Accepted]
Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib
Seulki Kim1, Tae Min Kim1,2, Dong-Wan Kim1,2, Soyeon Kim1, Miso Kim1, Yong-Oon Ahn1, Bhumsuk Keam1,2, Dae Seog Heo1,2
1Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
2Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

This study was presented in part at the EORTC-NCI-AACR Molecular Targets and Cancer Therapeutic Symposium (November 29-December 2, 2016), Munich, Germany.
Correspondence  Dong-Wan Kim ,Tel: 82-2-2072-2995 , Fax: 82-2-2072-2199, Email: kimdw@snu.ac.kr
Received: January 18, 2018;  Accepted: October 5, 2018.  Published online: October 10, 2018.
*Seulki Kim and Tae Min Kim contributed equally to this work.
Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been well elucidated. To understand the mechanisms of resistance and establish therapeutic strategies, we developed an in vitro model using the MET-amplified NSCLC cell line EBC-1.
Materials and Methods
We established capmatinib-resistant NSCLC cell lines and identified alternative signaling pathways using 3′ mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative polymerase chain reaction and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the resistant cell lines.
We found that EBC-CR1 showed an epidermal growth factor receptor (EGFR)‒dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells that had overexpression of EGFR-MET heterodimer dramatically responded to combined capmatinib with afatinib. In addition, EBC-CR3 cells derived from EBC-CR1 cells that activated EGFR with amplified phosphoinositide-3 kinase catalytic subunit α (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase α (PI3Kα) inhibitor.
Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients.
Key words: MET tyrosine kinase inhibitor, Capmatinib, MET amplification, Non-small cell lung carcinoma, Acquired resistance
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