title: Resistance to the c-Met inhibitor KRC-108 induces the epithelial transition of gastric cancer cells.
abstract: Investigation of the mechanisms of resistance to targeted therapies is essential as resistance acquired during treatment may lead to relapse or refractoriness to the therapy. Our previous study identified the small molecule KRC-108 as a result of efforts to find an anticancer agent with c-Met-inhibitory activity. In the present study, the changes accompanying resistance to KRC-108 were investigated in the gastric cancer cell line MKN-45 and its KRC-108-resistant clones by western blot and immunofluorescence analyses. Increased expression of the c-Met protein was observed in KRC-108-resistant cells compared with that of the parental cells, and the phosphorylation of c-Met also increased in cell lines resistant to KRC-108. Resistance to the c-Met inhibitor was associated with cell morphological changes: MKN-45 parental cells, which had a round and poorly differentiated morphology, were altered to exhibit an epithelial cell-like phenotype in KRC-108-resistant clones. Consistent with the transition to an epithelial morphology, the expression of E-cadherin was increased in resistant cells. Using immunoprecipitation, an interaction between E-cadherin and the c-Met protein was observed in the KRC-108-resistant cells. Immunohistochemical analysis of human gastric carcinoma tissues revealed the co-expression of E-cadherin and c-Met. These results suggest that the epithelial transition in KRC-108-resistant cells is mediated by recruiting E-cadherin to c-Met protein. Thus, the present study identified a mechanism used by cancer cells to confer resistance to anticancer agents.
authors.affiliation: Department of Pathology, School of Medicine, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea.
authors.forename: Dong Chul
authors.initials: DC
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea; Research Institute of Life Sciences, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea.
authors.forename: Kyeong Ryang
authors.initials: KR
authors.lastname: Park
authors.affiliation: College of Pharmacy, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea; Research Institute of Life Sciences, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea.
authors.forename: Yeon Ji
authors.initials: YJ
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea; Research Institute of Life Sciences, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea.
authors.forename: Hyonok
authors.initials: H
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea; Research Institute of Life Sciences, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Department of Theriogenology and Biotechnology, School of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea.
authors.forename: Gyu-Jin
authors.initials: GJ
authors.lastname: Rho
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 200-701, Republic of Korea.
authors.forename: Jongkook
authors.initials: J
authors.lastname: Lee
authors.affiliation: Innovative Drug Library Research Center, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Young-Dae
authors.initials: YD
authors.lastname: Gong
authors.affiliation: College of Pharmacy, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea; Research Institute of Life Sciences, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Han
keywords: E-cadherin; c-Met; drug resistance; epithelial transition