Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib

다국어 초록 (Multilingual 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 " (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase " (PI3K") 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 PI3K" inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients.

참고문헌 (Reference)

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