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The role of enhanced autophagy in acquired resistance to new B‐Raf inhibitor UI‐152
Author(s) -
Jang GunHee,
Ahn JunHo,
Lee Michael
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.994.4
Subject(s) - autophagy , apoptosis , mapk/erk pathway , drug resistance , melanoma , mek inhibitor , cell cycle , cancer research , mutant , chemistry , stimulation , biology , microbiology and biotechnology , signal transduction , biochemistry , gene , endocrinology , genetics
B‐Raf mutant melanomas have limited duration of clinical response with selective B‐Raf inhibitors because of rapidly acquired resistance. To investigate if chronic B‐Raf inhibition could lead to acquired drug resistance, we used chronic selection to establish B‐Raf(V600E) melanoma clones with acquired resistance to new B‐Raf inhibitor UI‐152. The A375P cells were highly sensitive to B‐Raf inhibition by UI‐152 (IC 50 ¡Ü 0.5 ¦ÌM), whereas A375P/Mdr cells that had been chronically treated with UI‐152 required higher doses of the drug for partial growth inhibition (IC 50 >; 20 ¦ÌM). The selected clones did not show re‐activation of the MAPK pathway, indicating that input from alternative, MAPK‐independent pathways induce B‐Raf inhibitor resistance mechanisms. Flow cytometric analysis showed that UI‐152 treatment induced G 0 /G 1 cell‐cycle arrest and decreased the percentage of cells in the S and G 2 /M phases. Few cells with GFP‐LC3 punctate dots were detected in A375 cells treated with UI‐152. Most surprisingly, the fraction of A375P/Mdr cells that underwent autophagy was significantly increased after treatment with UI‐152, suggesting that functional autophagy in response to UI‐152 may lead to cell survival. Vice versa, too little apoptosis was observed in A375P/Mdr cells. Taken together, our results suggest that the acquisition of resistance may be multi‐factorial and mediated by pathways other than the MAPK.