c-Met targeting enhances the effect of irradiation and chemical agents against malignant colon cells harboring a KRAS mutation

Yingbo Li; Jinxi Wang; Xing Gao; Weihua Han; Yongxiang Zheng; Huan Xu; Chuanling Zhang; Qiuchen He; Lihe Zhang; Zhongxin Li; Demin Zhou

doi:10.1371/journal.pone.0113186

c-Met targeting enhances the effect of irradiation and chemical agents against malignant colon cells harboring a KRAS mutation

PLoS One. 2014 Nov 26;9(11):e113186. doi: 10.1371/journal.pone.0113186. eCollection 2014.

Authors

Affiliations

¹ State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
² State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; Second Department of Surgery, the Fourth Hospital of Hebei Medical University, Hebei, China.
³ Second Department of Surgery, the Fourth Hospital of Hebei Medical University, Hebei, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Carcinoma / genetics
Carcinoma / metabolism
Carcinoma / pathology
Carcinoma / therapy*
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
Colonic Neoplasms / therapy*
Gamma Rays / therapeutic use
Gene Expression Regulation, Neoplastic*
HCT116 Cells
HEK293 Cells
Humans
Mice
Mice, Nude
Molecular Targeted Therapy
Mutation
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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 / genetics*
ras Proteins / metabolism

Substances

Antineoplastic Agents
KRAS protein, human
Proto-Oncogene Proteins
RNA, Small Interfering
Proto-Oncogene Proteins c-met
Proto-Oncogene Proteins p21(ras)
ras Proteins

Grants and funding

This work was supported by the National Basic Research Program of China (973 Program; Grant No. 2010CB12300) and the National Natural Science Foundation of China (Grants Nos. 20932001, 91029711, 81172332 and 81301881). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.