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 other
oncogenic growth factor receptors may serve as an underlying mechanism of resistance. In this
study, we analyzed the role of HER receptors, in particular HER3 and its ligand heregulin, in this
respect. This also included the chromatin-organizer protein SATB1, as an established regulator of
HER 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 inhibitor
treatment 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 receptor
HER3. This finding was determined as functionally relevant, since HER3 activation by HRG led
to partial MET inhibitor resistance, and MAPK/Akt signaling was even found enhanced upon
HRG+MET inhibitor treatment compared to HRG alone. SATB1 was identified as mediator of HER3
upregulation. Concomitantly, SATB1 knockdown prevented upregulation of HER3, thus abrogating
the HRG-promoted rescue from MET inhibition. Taken together, our results introduce the combined
HER3/MET inhibition as strategy to overcome resistance towards MET inhibitors.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:88726 |
| Date | 19 December 2023 |
| Creators | Jenke, Robert, Holzhäuser-Rein, Miriam, Mueller-Wilke, Stefanie, Lordick, Florian, Aigner, Achim, Büch, Thomas |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 82, 10.3390/ijms22010082 |
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