Reactivation of ERK and Akt confers resistance of mutant BRAF colon cancer cells to the HSP90 inhibitor AUY922
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Chun Yan Wang1,2, Su Tang Guo1,2, Jia Yu Wang1, Xu Guang Yan1, Margaret Farrelly1, Yuan Yuan Zhang3, Fen Liu1, Hamed Yari1, Ting La1, Fu Xi Lei1, Lei Jin3, Xu Dong Zhang1, Chen Chen Jiang3
1School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia
2Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, China
3School of Medicine and Public Health, The University of Newcastle, NSW, Australia
Chen Chen Jiang, email: Chenchen.Jiang@newcastle.edu.au
Xu Dong Zhang, email: Xu.Zhang@newcastle.edu.au
Keywords: colon cancer, mutant BRAF, heat shock protein 90, AUY922, CDC37
Received: May 20, 2016 Accepted: June 29, 2016 Published: July 06, 2016
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.
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