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BRAF inhibition upregulates a variety of receptor tyrosine kinases and their downstream effector Gab2 in colorectal cancer cell lines

Oncogene volume 37, pages 1576–1593 (2018)Cite this article

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Abstract

BRAF mutations occur in ~10% of colorectal cancer (CRC) and are associated with poor prognosis. Inhibitors selective for the BRAFV600E oncoprotein, the most common BRAF mutant, elicit only poor response rates in BRAF-mutant CRC as single agents. This unresponsiveness was mechanistically attributed to the loss of negative feedbacks on the epidermal growth factor receptor (EGFR) and initiated clinical trials that combine BRAF (and MEK) inhibitors, either singly or in combination, with the anti-EGFR antibodies cetuximab or panitumumab. First results of these combinatorial studies demonstrated improved efficacy, however, the response rates still were heterogeneous. Here, we show that BRAF inhibition leads to the upregulation of a variety of receptor tyrosine kinases (RTKs) in CRC cell lines, including not only the EGFR, but also human epidermal growth factor receptor (HER) 2 and HER3. Importantly, combination of the BRAF inhibitors (BRAFi) vemurafenib (PLX4032), dabrafenib, or encorafenib with inhibitors dually targeting the EGFR and HER2 (such as lapatinib, canertinib, and afatinib) significantly reduced the metabolic activity and proliferative potential of CRC cells. This re-sensitization was also observed after genetic depletion of HER2 or HER3. Interestingly, BRAF inhibitors did not only upregulate RTKs, but also increased the abundance of the GRB2-associated binders (Gab) 1 and Gab2, two important amplifiers of RTK signaling. An allele-specific shRNA-mediated knockdown of BRAFV600E revealed that Gab2 upregulation was directly dependent on the loss of the oncoprotein and was not caused by an “off-target” effect of these kinase inhibitors. Furthermore, Gab2 and Gab2-mediated Shp2 signaling were shown to be functionally important in BRAFi resistance. These findings highlight potential new escape mechanisms to these targeted therapies and indicate that a broad suppression of RTK signaling might be beneficial and should be taken into account in future research addressing targeted therapy in BRAF-mutant CRC.

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Acknowledgements

We thank Martin Köhler for valuable discussions, Roland Rad for sharing MouseT1 cells, and Silke Kowar for expert technical assistance. This work was supported by the German Research Foundation (DFG) through SFB 850, projects B4 (TB) and Z1 (HB and MB), a Heisenberg professorship to TB, EXC 294 BIOSS and the BMBF through e:Bio 0316184D, and MB within the framework of the e:Med research and funding concept, DeCaRe (FKZ 01ZX1409B).

Author contributions

RH, SH, and TB designed the research and performed data analysis. RH, SH, and MH performed the experiments. HB and MB analyzed the microarray data. RH wrote the manuscript together with TB.

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Authors and Affiliations

  1. Signal Transduction in Tumour Development and Drug Resistance Group, Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Ricarda Herr, Sebastian Halbach, Miriam Heizmann & Tilman Brummer

  2. Faculty of Biology, University of Freiburg, Freiburg, Germany

    Miriam Heizmann

  3. Systems Biology of the Cellular Microenvironment, IMMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Hauke Busch & Melanie Boerries

  4. Institute of Experimental Dermatology and Institute of Cardiogenetics, University of Lübeck, Lübeck, Germany

    Hauke Busch

  5. German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Melanie Boerries & Tilman Brummer

  6. Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany

    Melanie Boerries & Tilman Brummer

  7. Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany

    Tilman Brummer

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Herr, R., Halbach, S., Heizmann, M. et al. BRAF inhibition upregulates a variety of receptor tyrosine kinases and their downstream effector Gab2 in colorectal cancer cell lines. Oncogene 37, 1576–1593 (2018). https://doi.org/10.1038/s41388-017-0063-5

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