Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in <i>NRAS</i>-mutated RMS cells <i>in vitro</i> and <i>in vivo</i><i>NRAS</i>- or <i>HRAS</i>-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than <i>RAS</i> wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in <i>NRAS</i>-mutated than <i>RAS</i> wild-type RMS tumors <i>in vivo</i> We identified BCL-2-modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased.
In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer.
We showed that the introduction of Gas5 by plasmid transfection increased the expression of tumor suppressor Bcl-2-modifying factor (bmf) and Plexin C1 via directly targeting and reducing the expression of miR-222.