RRC ID 77170
Author Funakoshi Y, Mukohara T, Tomioka H, Ekyalongo RC, Kataoka Y, Inui Y, Kawamori Y, Toyoda M, Kiyota N, Fujiwara Y, Minami H.
Title Excessive MET signaling causes acquired resistance and addiction to MET inhibitors in the MKN45 gastric cancer cell line.
Journal Invest New Drugs
Abstract The clinical efficacy of MET tyrosine kinase inhibitors (MET-TKIs) is hindered by the emergence of acquired resistance, presenting an obstacle to drug discovery. To clarify the mechanisms underlying acquired resistance to MET-TKIs, we established resistance models by continuous exposure of the MET-amplified gastric cancer cell line MKN45 to MET-TKIs, PHA665752 (MKN45-PR) and GSK1363089 (MKN45-GR). Baseline expression and phosphorylation of MET were elevated in MKN45-PR and MKN45-GR compared to MKN45 cells, and higher concentrations of MET-TKIs were required to inhibit MET phosphorylation compared to parental cells. Alterations in MET previously associated with resistance to MET-TKIs were observed in resistant cells, including elevated MET copy number, observed in both resistant lines compared to MKN45 cells, and the Y1230H mutation, detected in MKN45-PR cells. Notably, the growth of resistant lines was lower in the absence of MET-TKIs, suggesting "addiction" to inhibitors. While MKN45-PR cells exhibited a higher S-phase fraction in the absence of PHA665752, bromodeoxyuridine (BrdU) uptake was identical. Baseline phosphorylation of ATR, Chk1 and p53 and p21(waf1/Cip1) expression was higher in MKN45-PR compared to MKN45 cells, and levels were reduced to those observed in untreated MKN45 cells following PHA665752 treatment. Furthermore, targeted knockdown of MET enhanced the growth of MKN45-PR cells. These findings suggest that alterations in MET leading to acquired MET-TKI resistance, may cause excessive MET signaling, subsequent replication stress and DNA damage response, and intra-S-phase arrest in the absence of MET-TKIs. Thus, partial MET inhibition is necessary for resistant cells to proliferate, a phenomenon we refer to as MET-TKI "addiction".
Volume 31(5)
Pages 1158-68
Published 2013-10-1
DOI 10.1007/s10637-013-9959-2
PMID 23568717
MeSH Antineoplastic Agents / pharmacology* Cell Cycle / drug effects Cell Line, Tumor Cell Proliferation / drug effects DNA Damage Drug Resistance, Neoplasm / physiology* Humans Indoles / pharmacology* Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-met / antagonists & inhibitors Proto-Oncogene Proteins c-met / genetics Proto-Oncogene Proteins c-met / metabolism* RNA, Small Interfering / genetics Signal Transduction Stomach Neoplasms Sulfones / pharmacology*
IF 3.525
Human and Animal Cells MKN45(RCB1001)