title: Reactivation of ERK and Akt confers resistance of mutant BRAF colon cancer cells to the HSP90 inhibitor AUY922.
abstract: Oncogenic mutations of BRAF occur in approximately 10% of colon cancers and are associated with their resistance to clinically available therapeutic drugs and poor prognosis of the patients. Here we report that colon cancer cells with mutant BRAF are also resistant to the heat shock protein 90 (HSP90) inhibitor AUY922, and that this is caused by rebound activation of ERK and Akt. Although AUY922 triggered rapid reduction in ERK and Akt activation in both wild-type and mutant BRAF colon cancer cells, activation of ERK and Akt rebounded shortly in the latter leading to resistance of the cells to AUY922-induced apoptosis. Reactivation of ERK was associated with the persistent expression of mutant BRAF, which, despite being a client of HSP90, was only partially degraded by AUY922, whereas reactivation of Akt was related to the activity of the HSP90 co-chaperone, cell division cycle 37 (CDC37), in that knockdown of CDC37 inhibited Akt reactivation in mutant colon cancer cells treated with AUY922. In support, as a HSP90 client protein, Akt was only diminished by AUY922 in wild-type but not mutant BRAF colon cancer cells. Collectively, these results reveal that reactivation of ERK and Akt associated respectively with the activity of mutant BRAF and CDC37 renders mutant BRAF colon cancer cells resistant to AUY922, with implications of co-targeting mutant BRAF and/or CDC37 and HSP90 in the treatment of mutant BRAF colon cancers.
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.|Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, China.
authors.forename: Chun Yan
authors.initials: CY
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.|Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, China.
authors.forename: Su Tang
authors.initials: ST
authors.lastname: Guo
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Jia Yu
authors.initials: JY
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Xu Guang
authors.initials: XG
authors.lastname: Yan
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Margaret
authors.initials: M
authors.lastname: Farrelly
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW, Australia.
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Fen
authors.initials: F
authors.lastname: Liu
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Hamed
authors.initials: H
authors.lastname: Yari
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Ting
authors.initials: T
authors.lastname: La
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Fu Xi
authors.initials: FX
authors.lastname: Lei
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW, Australia.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia.
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW, Australia.
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
mesh_terms: D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D018833:Chaperonins / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012118:Resorcinols / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D018833:Chaperonins
keywords: AUY922; CDC37; colon cancer; heat shock protein 90; mutant BRAF