Publications
Detailed Information
Acquired resistance mechanisms to capmatinib, a MET inhibitor in MET-amplified non-small cell lung cancer cells
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 김동완 | - |
dc.contributor.author | Kim Seulki | - |
dc.date.accessioned | 2017-07-19T10:08:06Z | - |
dc.date.available | 2017-07-19T10:08:06Z | - |
dc.date.issued | 2017-02 | - |
dc.identifier.other | 000000140818 | - |
dc.identifier.uri | https://hdl.handle.net/10371/132316 | - |
dc.description | 학위논문 (석사)-- 서울대학교 대학원 : 종양생물학전공, 2017. 2. 김동완. | - |
dc.description.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 elucidated. Capmatinib (INC280, Novartis) is a highly potent and selective small molecule MET-TKI. To understand the mechanisms of resistance to MET-TKIs and establish therapeutic strategies, we developed an in vitro model using capmatinib-resistant cell lines (EBC-CR1, CR2, and CR3) derived from the MET-amplified NSCLC cell line EBC-1.
Methods: We established capmatinib-resistant NSCLC cell lines from the MET-amplified NSCLC cell line EBC-1 and identified alternative signaling pathways using 3mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative PCR and cell proliferation assay | - |
dc.description.abstract | activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the EBC-CR1, -CR2, and -CR3 resistant cell lines.
Results: We found that epidermal growth factor (EGFR) mRNA expression and protein activation were increased in EBC-CR1–3 cells compared to EBC-1 cells. EBC-CR1 cells showed EGFR-dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells, which overexpressed the EGFR-MET heterodimer, responded dramatically to the combination of capmatinib and the phosphoinositide-3 kinase catalytic subunit α (PIK3CA) inhibitor afatinib. In addition, EBC-CR3 cells, which had activated EGFR along with amplified PIK3CA, were sensitive to the combination of afatinib and the PI3Kα inhibitor BYL719. Conclusions: 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 an effective therapeutic strategy in MET-TKI-resistant NSCLC patients. | - |
dc.description.tableofcontents | 1. Introduction 1
2. Materials and methods 3 3. Results 8 3.1 Establishment of EBC-1 cells with acquired resistance to capmatinib 8 3.2 Acquired resistant mechanisms to capmatinib were associated with EGFR kinase pathway 12 3.3 Increased MET and EGFR heterodimerization caused acquired resistance to MET-TKI 20 3.4 Acquired resistance to EGFR-TKI beyond MET-TKI resistance 25 4. Discussion 30 5. Reference 37 6. Abstract in Korean 40 | - |
dc.format | application/pdf | - |
dc.format.extent | 2254950 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | non-small cell lung cancer | - |
dc.subject | acquired resistance | - |
dc.subject | MET amplification | - |
dc.subject | capmatinib | - |
dc.subject.ddc | 616 | - |
dc.title | Acquired resistance mechanisms to capmatinib, a MET inhibitor in MET-amplified non-small cell lung cancer cells | - |
dc.type | Thesis | - |
dc.description.degree | Master | - |
dc.citation.pages | ⅳ, 41 | - |
dc.contributor.affiliation | 의과대학 협동과정 종양생물학전공 | - |
dc.date.awarded | 2017-02 | - |
- Appears in Collections:
- Files in This Item:
Item View & Download Count
Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.