Back to Search
Start Over
Excessive MET signaling causes acquired resistance and addiction to MET inhibitors in the MKN45 gastric cancer cell line.
- Source :
-
Investigational new drugs [Invest New Drugs] 2013 Oct; Vol. 31 (5), pp. 1158-68. Date of Electronic Publication: 2013 Apr 09. - Publication Year :
- 2013
-
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".
- Subjects :
- Cell Cycle drug effects
Cell Line, Tumor
Cell Proliferation drug effects
DNA Damage
Humans
Proto-Oncogene Proteins c-met antagonists & inhibitors
Proto-Oncogene Proteins c-met genetics
RNA, Small Interfering genetics
Signal Transduction
Stomach Neoplasms
Antineoplastic Agents pharmacology
Drug Resistance, Neoplasm physiology
Indoles pharmacology
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-met metabolism
Sulfones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 31
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 23568717
- Full Text :
- https://doi.org/10.1007/s10637-013-9959-2