Beschreibung:
MET-amplified gastric cancer cells are extremely sensitive to MET inhibition in vitro,whereas clinical efficacy of MET inhibitors is disappointing. The compensatory activation of otheroncogenic growth factor receptors may serve as an underlying mechanism of resistance. In thisstudy, we analyzed the role of HER receptors, in particular HER3 and its ligand heregulin, in thisrespect. This also included the chromatin-organizer protein SATB1, as an established regulator ofHER expression in other tumor entities. In a panel of MET-amplified gastric carcinoma cell lines,cell growth under anchorage-dependent and independent conditions was studied upon inhibitortreatment or siRNA-mediated knockdown. Expression analyses were performed using RT-qPCR,FACS, and immunoblots. Signal transduction was monitored via antibody arrays and immunoblots.As expected, MET inhibition led to a growth arrest and inhibition of MAPK signaling. Strikingly,however, this was accompanied by a rapid and profound upregulation of the oncogenic receptorHER3. This finding was determined as functionally relevant, since HER3 activation by HRG ledto partial MET inhibitor resistance, and MAPK/Akt signaling was even found enhanced uponHRG+MET inhibitor treatment compared to HRG alone. SATB1 was identified as mediator of HER3upregulation. Concomitantly, SATB1 knockdown prevented upregulation of HER3, thus abrogatingthe HRG-promoted rescue from MET inhibition. Taken together, our results introduce the combinedHER3/MET inhibition as strategy to overcome resistance towards MET inhibitors.