Resistance to dasatinib is associated with the activation of Akt in oral squamous cell carcinoma

Abstract

Objectives:Overexpression and aberrant activation of Src promote the development of oral squamous cell carcinoma (OSCC), thus therapies targeting Src-related kinases may afford an improvement in patient survival. However, limited clinical activity of the Src-targeted drug, dasatinib, in cancer patients warrants further investigation to better understand the underlying basis of resistance to dasatinib in OSCC.Methods:Response to dasatinib was evaluated in a panel of oral cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, DNA synthesis, cell cycle and apoptosis analysis. The underlying mechanism of drug response was investigated using immunoblotting. Xenograft models were used to test efficacy.Results:All cell lines were sensitive to dasatinib (IC50 < 250 nM), but this was not associated with CDKN2a/p14ARF mutations. Dasatinib-induced cell cycle arrest and apoptosis, while inhibiting Src, Akt and FAK activity in all lines tested. However, dasatinib failed to inhibit tumour growth in xenograft models and treated tissues showed Akt activity despite the loss of Src activity.Conclusions:Our data revealed that reactivation of Akt (Ser473) could be a compensatory mechanism that bypasses Src inhibition by dasatinib, providing important clues that could improve treatment strategies to overcome dasatinib resistance.