Dasatinib sensitises KRAS-mutant cancer cells to mitogen-activated protein kinase kinase inhibitor via inhibition of TAZ activity

2018
Abstract Purpose Oncogenic KRASmutations occur frequently in solid tumours, but no clinically applicable targeted strategy is yet available for treating human cancers with mutant KRAS. Here we aimed to identify a strategy for the treatment of KRAS-driven cancers. Experimental Design Cell viability and colony forming assays were used to assess the in vitro effect of dasatiniband trametinibas single agents or in combination. Western blot was used to analyse the phosphorylated protein and total protein levels. Xenograft models were used to evaluate the in vivo effect of drug combination on KRAS-driven tumour growth. Results Here, we report the discovery of a synergistic interaction between dasatinib(ABL and SRC family kinaseinhibitor) and the mitogen-activated protein kinase kinase( MEK) inhibitor trametinibin KRAS-mutant cancer cells. We demonstrated that dasatinibenhanced the antitumour effect of trametinibagainst the KRAS-mutant cancer models both in vitro and in vivo , and the combination resulted in a significant reduction of cytoplasmic and nucleic TAZ protein level, and therefore decreased downstream protein levels of YAP/TAZ signalling pathway. Furthermore, direct knockdown of TAZ by small interfering RNA was able to increase the sensitivity of KRAS-mutant cells to trametinibtreatment. Conclusion These results indicate that dasatinibenhances the antitumour activity of MEK inhibitorthrough inhibition of TAZ activity and identify dasatiniband trametinibcombination as a potential strategy for the treatment of KRAS-driven cancers.
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