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.
Highlights
Despite recent advances in the treatment of colon cancer, the overall survival of patients with metastatic colon cancers remains disappointing [1,2,3]
Since cell division cycle 37 (CDC37) interacts with protein kinases and can stabilize and activate clients in concert with heat shock protein 90 (HSP90) or independently of HSP90 [23,24,25,26], we investigated whether CDC37 is involved in reactivation of Akt in mutant BRAF colon cancer cells treated with AUY922
Oncogenic mutations of BRAF are only seen in a small proportion of colon cancers, they pose a great challenge in the treatment of the disease, in that colon cancers with mutations in BRAF, similar to those with mutations in KRAS, are resistant to conventional chemotherapeutic drugs and agents targeting epidermal growth factor receptor (EGFR) [4,5,6, 38]
Summary
Despite recent advances in the treatment of colon cancer, the overall survival of patients with metastatic colon cancers remains disappointing [1,2,3]. Activating mutations of BRAF (BRAFV600E) are found only in a small proportion of colon cancers, this poses a great challenge in the quest for a better outcome of the patients, in that BRAF mutations, like mutations in KRAS, are associated with resistance of colon cancer to conventional chemotherapeutic drugs and agents targeting the epidermal growth factor receptor (EGFR) [4,5,6]. Mutant BRAF is a client protein of HSP90, whereas HSP90-mediated chaperoning is not required for stabilization of wild-type BRAF [17, 18]. This suggests that HSP90 inhibitors may be of particular importance in the treatment of colon cancers carrying mutant BRAF
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