Inhibitors of Heat Shock Proteins

Heat shock proteins (HSP) are a class of functionally related proteins involved in the folding and unfolding of other proteins, including oncoproteins. Their expression is increased when cells are exposed to stress. NVP-AUY922, an HSP90 inhibitor, was shown to inhibit proliferation of oral squamous cell carcinoma cell lines. Antitumor activity was mediated by the degradation of client proteins inducing ErbB2, p-Akt, p-S6, HIF1-a and VEGF and increased expression of cleaved caspase-3 and apoptosis (Okui et al. 2011). Suppression of p-Akt and VEGF expression in a xenograft model was also documented after administration of the HSP90 inhibitor (Okui et al. 2011). Another group showed radiosensitization in a human SCCHN xenograft model treated by the same HSP 90 inhibitor (Zaidi et al.

2012). Interaction of HSP90 with EGFR was found to be critical for maintaining receptor stability as well as growth of EGFR-dependent cancer (Ahsan et al. 2012). These findings support the potential role of HSP90 inhibitors for the treatment of SCCHN. An ongoing study is investigating the combination of cetuximab and IPI-926, an HSP inhibitor, in patients with R/M SCCHN (NCT01255800).

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