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Anti-tumor effects of NVP-BKM120 alone or in combination with MEK162 in biliary tract cancer

Cited 9 time in Web of Science Cited 6 time in Scopus
Authors
Jin, Ling; Jin, Mei-hua; Nam, Ah-Rong; Park, Ji-Eun; Bang, Ju-Hee; Oh, Do Yeun; Bang, Yung Jue
Issue Date
2017-12
Citation
Cancer Letters, Vol.411, pp.162-170
Keywords
PI3K inhibitorMEK inhibitorK-RasBiliary tract cancer
Abstract
There are currently no clinically validated therapeutic targets for biliary tract cancer (BTC). Despite promising results in other cancers, compounds targeting the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, alone or in combination with Ras/Raf/MEK pathway inhibitors, have not been evaluated in BTC. Here, we examined the effects of a pan-PI3K inhibitor (BKM120) with or without a MEK inhibitor (MEK162), on eight human BTC cell lines carrying mutations in K-Ras and/or the PI3K catalytic subunit, P13KCA. BKM120 inhibited the colony-forming ability and migration of BTC cells carrying wild-type (WT) PI3KCA and either mutant (MT) or WT K-Ras, but not of cells carrying mutations in both genes. In K-Ras-WT cells, BKM120 decreased the phosphorylation of Akt, its downstream effector kinase p70S6K, and the translational repressor 4E-BP1. Interestingly, BKM120 did not induce cell cycle arrest or suppress PI3K signaling via restoration of p-4E-BP1 in cells with PIK3CA and K-Ras double mutations. Notably, the resistance of dual K-Ras/PI3KCA-mutant cells to BKM120 was overcome by treatment with a combination of BKM120 and MEK162. Our findings thus support the clinical development of BKM120 monotherapy or BKM120/MEK162 combination therapy for the treatment of BTC. (c) 2017 Elsevier B.V. All rights reserved.
ISSN
0304-3835
URI
https://hdl.handle.net/10371/173169
DOI
https://doi.org/10.1016/j.canlet.2017.10.002
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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