Acquired resistance of MET-amplified non-small cell lung cancer cells to the MET inhibitor capmatinib

Seulki Kim, Tae Min Kim, Dong Wan Kim, Soyeon Kim, Miso Kim, Yong Oon Ahn, Bhumsuk Keam, Dae Seog Heo

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)951-962
Number of pages12
JournalCancer Research and Treatment
Volume51
Issue number3
DOIs
StatePublished - 1 Jul 2019

Fingerprint

Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
1-Phosphatidylinositol 4-Kinase
Cell Line
Protein-Tyrosine Kinases
Receptor Protein-Tyrosine Kinases
Epithelial-Mesenchymal Transition
Catalytic Domain
Therapeutics
Cell Proliferation
Polymerase Chain Reaction
Messenger RNA
Growth
BIBW 2992

Keywords

  • Acquired resistance
  • Capmatinib
  • MET amplification
  • MET tyrosine kinase inhibitor
  • Non-small cell lung carcinoma

Cite this

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title = "Acquired resistance of MET-amplified non-small cell lung cancer cells to the MET inhibitor capmatinib",
abstract = "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.",
keywords = "Acquired resistance, Capmatinib, MET amplification, MET tyrosine kinase inhibitor, Non-small cell lung carcinoma",
author = "Seulki Kim and Kim, {Tae Min} and Kim, {Dong Wan} and Soyeon Kim and Miso Kim and Ahn, {Yong Oon} and Bhumsuk Keam and Heo, {Dae Seog}",
year = "2019",
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pages = "951--962",
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Acquired resistance of MET-amplified non-small cell lung cancer cells to the MET inhibitor capmatinib. / Kim, Seulki; Kim, Tae Min; Kim, Dong Wan; Kim, Soyeon; Kim, Miso; Ahn, Yong Oon; Keam, Bhumsuk; Heo, Dae Seog.

In: Cancer Research and Treatment, Vol. 51, No. 3, 01.07.2019, p. 951-962.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Acquired resistance of MET-amplified non-small cell lung cancer cells to the MET inhibitor capmatinib

AU - Kim, Seulki

AU - Kim, Tae Min

AU - Kim, Dong Wan

AU - Kim, Soyeon

AU - Kim, Miso

AU - Ahn, Yong Oon

AU - Keam, Bhumsuk

AU - Heo, Dae Seog

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

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KW - MET amplification

KW - MET tyrosine kinase inhibitor

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