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c-Met targeting enhances the effect of irradiation and chemical agents against malignant colon cells harboring a KRAS mutation.
- Source :
-
PloS one [PLoS One] 2014 Nov 26; Vol. 9 (11), pp. e113186. Date of Electronic Publication: 2014 Nov 26 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- Although EGFR-targeted therapy has been beneficial to colorectal cancer patients, several studies have showed this clinical benefit was restricted to patients with wild-type KRAS exon 2 colorectal cancer. Therefore, it is crucial to explore efficient treatment strategies in patients with KRAS mutations. c-Met is an emerging target for the development of therapeutics against colorectal cancer. In this study, we first used the SW620 cell line, which has an activating KRAS mutation, to generate a stable cell line with conditional regulation of c-Met, which is an essential gene for growth and an oncogene. Using this approach, we evaluated the benefits of combined c-Met-targeted therapy with irradiation or chemical agents. In this cell line, we observed that the proliferation and migration of SW620 cells were reduced by the induction of c-Met shRNA. Furthermore, c-Met knockdown enhanced the anti-proliferative effects of 5-FU and Taxol but not cisplatin, irinotecan or sorafenib. These enhancements were also observed in another colon cancer cells line HCT-116, which also has a KRAS mutation. The response of SW620 cells to irradiation was also enhanced by c-Met knockdown. This method and obtained data might have important implications for exploring the combinatory effects of targeted therapies with conventional medications. Moreover, the data suggested that the combination of c-Met-targeted therapy with chemotherapy or irradiation might be an effective strategy against colorectal cancer harboring a KRAS mutation.
- Subjects :
- Animals
Carcinoma genetics
Carcinoma metabolism
Carcinoma pathology
Cell Line, Tumor
Cell Movement drug effects
Cell Movement radiation effects
Cell Survival drug effects
Cell Survival radiation effects
Colonic Neoplasms genetics
Colonic Neoplasms metabolism
Colonic Neoplasms pathology
Gamma Rays therapeutic use
HCT116 Cells
HEK293 Cells
Humans
Mice
Mice, Nude
Molecular Targeted Therapy
Mutation
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-met genetics
Proto-Oncogene Proteins c-met metabolism
Proto-Oncogene Proteins p21(ras)
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
Signal Transduction
Tumor Burden drug effects
Tumor Burden radiation effects
Xenograft Model Antitumor Assays
ras Proteins metabolism
Antineoplastic Agents pharmacology
Carcinoma therapy
Colonic Neoplasms therapy
Gene Expression Regulation, Neoplastic
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins c-met antagonists & inhibitors
ras Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25427200
- Full Text :
- https://doi.org/10.1371/journal.pone.0113186