Suppressing HER3 signaling by interfering with its Sec61-dependent contranlational translocation

 

The human epidermal growth factor receptor (HER) family, including epidermal growth factor receptor (EGFR), HER2, HER3 and HER4, is frequently involved in the mechanism of many types of human cancers. HER3 is a potent activator of PI3K/Akt signaling, which strongly promotes cancer cell survival. However, as an allosteric activator, HER3 lacks catalytic kinase activity and cannot be inhibited by small-molecule ATP-analog tyrosine kinase inhibitors. Ruiz-Saenz et al. demonstrated a novel approach specifically reduces HER3 expression. The article was published online in Oncogene, recently.

 

CT8, a small-molecule contransin, binds to the Sec61 translocon, which regulate transportation into or out of the endoplasmic reticulum (ER), to inhibit cotranslational translocation of nascent HER3 protein, leads to the degradation of HER3 specifically. In combination with lapatinib, CT8 treatment enhanced the cell apoptotic effects though the suppression of HER3 induction in HER2-amplified cancers. As useful regulators, contransins have structure-dependent target selectivities, which can be narrowed through structure-function studies. The novel approach may provide an efficient therapeutic strategy against cancer involved HER3 signaling.

 

Reference:
Oncogene. 2015 Jan 26. doi: 10.1038/onc.2014.455.

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