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Dovitinib (TKI258), a multi-target angiokinase inhibitor, is effective regardless of KRAS or BRAF mutation status in colorectal cancer

Authors
 Choong-Kun Lee  ;  Myung Eun Lee  ;  Won Suk Lee  ;  Jeong Min Kim  ;  Kyu Hyun Park  ;  Tae Soo Kim  ;  Kang Young Lee  ;  Joong Bae Ahn  ;  Hyun Cheol Chung  ;  Sun Young Rha 
Citation
 AMERICAN JOURNAL OF CANCER RESEARCH, Vol.5(1) : 72-86, 2015 
Journal Title
 AMERICAN JOURNAL OF CANCER RESEARCH 
ISSN
 2156-6976 
Issue Date
2015
Keywords
BRAF ; Colorectal cancer ; Dovitinib (TKI258) ; FGFR ; KRAS ; multi-target angiokinase inhibitor
Abstract
INTRODUCTION: We aimed to determine whether KRAS and BRAF mutant colorectal cancer (CRC) cells exhibit distinct sensitivities to the multi-target angiokinase inhibitor, TKI258 (dovitinib). MATERIALS AND METHODS: We screened 10 CRC cell lines by using receptor tyrosine kinase (RTK) array to identify activated RTKs. MTT assays, anchorage-independent colony-formation assays, and immunoblotting assays were performed to evaluate the in vitro anti-tumor effects of TKI258. In vivo efficacy study followed by pharmacodynamic evaluation was done. RESULTS: Fibroblast Growth Factor Receptor 1 (FGFR1) and FGFR3 were among the most highly activated RTKs in CRC cell lines. In in vitro assays, the BRAF mutant HT-29 cells were more resistant to the TKI258 than the KRAS mutant LoVo cells. However, in xenograft assays, TKI258 equally delayed the growth of tumors induced by both cell lines. TUNEL assays showed that the apoptotic index was unchanged following TKI258 treatment, but staining for Ki-67 and CD31 was substantially reduced in both xenografts, implying an anti-angiogenic effect of the drug. TKI258 treatment was effective in delaying CRC tumor growth in vivo regardless of the KRAS and BRAF mutation status. CONCLUSIONS: Our results identify FGFRs as potential targets in CRC treatment and suggest that combined targeting of multiple RTKs with TKI258 might serve as a novel approach to improve outcome of patients with CRC.
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DOI
2015
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jung Min(김정민)
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Ahn, Joong Bae(안중배) ORCID logo https://orcid.org/0000-0001-6787-1503
Lee, Kang Young(이강영)
Lee, Myung Eun(이명은)
Lee, Choong Kun(이충근)
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/139768
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