title: c-Met targeting enhances the effect of irradiation and chemical agents against malignant colon cells harboring a KRAS mutation.
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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jinxi
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xing
authors.initials: X
authors.lastname: Gao
authors.affiliation: Second Department of Surgery, the Fourth Hospital of Hebei Medical University, Hebei, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Han
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Chuanling
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Qiuchen
authors.initials: Q
authors.lastname: He
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Lihe
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Demin
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005720:Gamma Rays / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins