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SATB1-Mediated Upregulation of the Oncogenic Receptor Tyrosine Kinase HER3 Antagonizes MET Inhibition in Gastric Cancer Cells

1
University Cancer Center Leipzig (UCCL), University Hospital Leipzig, D-04103 Leipzig, Germany
2
Clinical Pharmacology, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Medical Faculty, Leipzig University, D-04107 Leipzig, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(1), 82; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010082
Received: 26 November 2020 / Revised: 16 December 2020 / Accepted: 17 December 2020 / Published: 23 December 2020
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. View Full-Text
Keywords: gastric cancer; HER3; heregulin; MET; SATB1 gastric cancer; HER3; heregulin; MET; SATB1
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MDPI and ACS Style

Jenke, R.; Holzhäuser-Rein, M.; Mueller-Wilke, S.; Lordick, F.; Aigner, A.; Büch, T. SATB1-Mediated Upregulation of the Oncogenic Receptor Tyrosine Kinase HER3 Antagonizes MET Inhibition in Gastric Cancer Cells. Int. J. Mol. Sci. 2021, 22, 82. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010082

AMA Style

Jenke R, Holzhäuser-Rein M, Mueller-Wilke S, Lordick F, Aigner A, Büch T. SATB1-Mediated Upregulation of the Oncogenic Receptor Tyrosine Kinase HER3 Antagonizes MET Inhibition in Gastric Cancer Cells. International Journal of Molecular Sciences. 2021; 22(1):82. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010082

Chicago/Turabian Style

Jenke, Robert, Miriam Holzhäuser-Rein, Stefanie Mueller-Wilke, Florian Lordick, Achim Aigner, and Thomas Büch. 2021. "SATB1-Mediated Upregulation of the Oncogenic Receptor Tyrosine Kinase HER3 Antagonizes MET Inhibition in Gastric Cancer Cells" International Journal of Molecular Sciences 22, no. 1: 82. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010082

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