RRC ID 55029
Author Ito T, Kumagai Y, Itano K, Maruyama T, Tamura K, Kawasaki S, Suzuki T, Murakami Y.
Title Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification.
Journal Biochem Biophys Res Commun
Abstract Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5-22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.
Volume 511(3)
Pages 544-550
Published 2019-4-9
DOI 10.1016/j.bbrc.2019.02.086
PII S0006-291X(19)30281-5
PMID 30824185
MeSH Adenocarcinoma of Lung / drug therapy* Adenocarcinoma of Lung / genetics Antineoplastic Agents / pharmacology* Cell Line, Tumor Computer Simulation Drug Resistance, Neoplasm Gefitinib / pharmacology* Gene Amplification Humans Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Models, Biological Proto-Oncogene Proteins c-met / genetics*
IF 2.705
Times Cited 5
DNA material pENTR4-H1 (RDB04395) CS-RfA-CG (RDB04390) pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)