Human melanoma cells resistant to MAPK inhibitors can be effectively targeted by inhibition of the p90 ribosomal S6 kinase
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Corinna Kosnopfel1, Tobias Sinnberg1, Birgit Sauer1, Heike Niessner1, Anja Schmitt2, Elena Makino1, Andrea Forschner1, Stephan Hailfinger2, Claus Garbe1, Birgit Schittek1
1Division of Dermatooncology, Department of Dermatology, University of Tübingen, Tübingen, Germany
2Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
Birgit Schittek, email: firstname.lastname@example.org
Keywords: melanoma, MAPK inhibition, therapy resistance, p90 ribosomal S6 kinase, YB-1
Received: January 18, 2017 Accepted: March 06, 2017 Published: March 15, 2017
The clinical availability of small molecule inhibitors specifically targeting mutated BRAF marked a significant breakthrough in melanoma therapy. Despite a dramatic anti-tumour activity and improved patient survival, rapidly emerging resistance, however, greatly limits the clinical benefit. The majority of the already described resistance mechanisms involve a reactivation of the MAPK signalling pathway. The p90 ribosomal S6 kinase (RSK), a downstream effector of the MAPK signalling cascade, has been reported to enhance survival of melanoma cells in response to chemotherapy. Here, we can show that RSK activity is significantly increased in human melanoma cells with acquired resistance to the BRAFV600E/K inhibitor vemurafenib. Interestingly, inhibition of RSK signalling markedly impairs the viability of vemurafenib resistant melanoma cells and is effective both in two-dimensional and in three-dimensional culture systems, especially in a chronic, long-term application. The effect of RSK inhibition can be partly replicated by downregulation of the well-known RSK target, Y-box binding protein 1 (YB-1). Intriguingly, RSK inhibition also retains its efficacy in melanoma cells with combined resistance to vemurafenib and the MEK inhibitor trametinib. These data suggest that active RSK signalling might be an attractive novel therapeutic target in melanoma with acquired resistance to MAPK pathway inhibitors.
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