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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