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Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib / Journal of the Korean Cancer Association, 대한암학회지
Cancer Research and Treatment ; : 951-962, 2019.
Article in English | WPRIM | ID: wpr-763184
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.
Subject(s)

Full text: Available Index: WPRIM (Western Pacific) Main subject: Parents / Phosphotransferases / In Vitro Techniques / Protein-Tyrosine Kinases / RNA, Messenger / Cell Line / Polymerase Chain Reaction / Carcinoma, Non-Small-Cell Lung / Catalytic Domain / Cell Proliferation Type of study: Prognostic study Limits: Humans Language: English Journal: Cancer Research and Treatment Year: 2019 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Parents / Phosphotransferases / In Vitro Techniques / Protein-Tyrosine Kinases / RNA, Messenger / Cell Line / Polymerase Chain Reaction / Carcinoma, Non-Small-Cell Lung / Catalytic Domain / Cell Proliferation Type of study: Prognostic study Limits: Humans Language: English Journal: Cancer Research and Treatment Year: 2019 Type: Article