Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib
- Author:
Seulki KIM
1
;
Tae Min KIM
;
Dong Wan KIM
;
Soyeon KIM
;
Miso KIM
;
Yong Oon AHN
;
Bhumsuk KEAM
;
Dae Seog HEO
Author Information
- Publication Type:Original Article
- Keywords: MET tyrosine kinase inhibitor; Capmatinib; MET amplification; Non-small cell lung carcinoma; Acquired resistance
- MeSH: Carcinoma, Non-Small-Cell Lung; Catalytic Domain; Cell Line; Cell Proliferation; Humans; In Vitro Techniques; Parents; Phosphotransferases; Polymerase Chain Reaction; Protein-Tyrosine Kinases; Receptor, Epidermal Growth Factor; RNA, Messenger
- From:Cancer Research and Treatment 2019;51(3):951-962
- CountryRepublic of Korea
- Language:English
- Abstract: PURPOSE: 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. RESULTS: 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. CONCLUSION: 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.
