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Sci. Signal., 29 January 2013
Vol. 6, Issue 260, p. ra7
[DOI: 10.1126/scisignal.2003057]

RESEARCH ARTICLES

Vemurafenib Potently Induces Endoplasmic Reticulum Stress–Mediated Apoptosis in BRAFV600E Melanoma Cells

Daniela Beck1, Heike Niessner1, Keiran S. M. Smalley2, Keith Flaherty3, Kim H. T. Paraiso2, Christian Busch1, Tobias Sinnberg1, Sophie Vasseur4,5,6,7, Juan Lucio Iovanna4, Stefan Drießen8, Björn Stork8, Sebastian Wesselborg8, Martin Schaller1, Tilo Biedermann1, Jürgen Bauer1, Konstantinos Lasithiotakis1, Benjamin Weide1, Jürgen Eberle9, Birgit Schittek1, Dirk Schadendorf10, Claus Garbe1, Dagmar Kulms11,12, and Friedegund Meier1*

1 Division of Dermatologic Oncology, Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany.
2 Departments of Molecular Oncology and Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
3 Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
4 Centre de Recherche INSERM, 13288 Marseille, France.
5 Institut Paoli-Calmettes, 13288 Marseille, France.
6 Aix-Marseille University, 13288 Marseille, France.
7 CNRS, UMR7258, CRCM, 13288 Marseille, France.
8 Institute of Molecular Medicine, University Hospital Düsseldorf, 40225 Düsseldorf, Germany.
9 Department of Dermatology and Allergy, Skin Cancer Center Charité, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany.
10 Department of Dermatology, University of Essen, 45122 Essen, Germany.
11 Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany.
12 Experimental Dermatology, Department of Dermatology, TU-Dresden, 01307 Dresden, Germany.

Abstract: The V600E mutation in the kinase BRAF is frequently detected in melanomas and results in constitutive activation of BRAF, which then promotes cell proliferation by the mitogen-activated protein kinase signaling pathway. Although the BRAFV600E kinase inhibitor vemurafenib has remarkable antitumor activity in patients with BRAFV600E-mutated melanoma, its effects are limited by the onset of drug resistance. We found that exposure of melanoma cell lines with the BRAFV600E mutation to vemurafenib decreased the abundance of antiapoptotic proteins and induced intrinsic mitochondrial apoptosis. Vemurafenib-treated melanoma cells showed increased cytosolic concentration of calcium, a potential trigger for endoplasmic reticulum (ER) stress, which can lead to apoptosis. Consistent with an ER stress–induced response, vemurafenib decreased the abundance of the ER chaperone protein glucose-regulated protein 78, increased the abundance of the spliced isoform of the transcription factor X-box binding protein 1 (XBP1) (which transcriptionally activates genes involved in ER stress responses), increased the phosphorylation of the translation initiation factor eIF2α (which would be expected to inhibit protein synthesis), and induced the expression of ER stress–related genes. Knockdown of the ER stress response protein activating transcription factor 4 (ATF4) significantly reduced vemurafenib-induced apoptosis. Moreover, the ER stress inducer thapsigargin prevented invasive growth of tumors formed from vemurafenib-sensitive melanoma cells in vivo. In melanoma cells with low sensitivity or resistance to vemurafenib, combination treatment with thapsigargin augmented or induced apoptosis. Thus, thapsigargin or other inducers of ER stress may be useful in combination therapies to overcome vemurafenib resistance.

* To whom correspondence should be addressed. E-mail: friedegund.meier{at}t-online.de

Citation: D. Beck, H. Niessner, K. S. M. Smalley, K. Flaherty, K. H. T. Paraiso, C. Busch, T. Sinnberg, S. Vasseur, J. L. Iovanna, S. Drießen, B. Stork, S. Wesselborg, M. Schaller, T. Biedermann, J. Bauer, K. Lasithiotakis, B. Weide, J. Eberle, B. Schittek, D. Schadendorf, C. Garbe, D. Kulms, F. Meier, Vemurafenib Potently Induces Endoplasmic Reticulum Stress–Mediated Apoptosis in BRAFV600E Melanoma Cells. Sci. Signal. 6, ra7 (2013).

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