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Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma

Cell Death & Differentiation (2018) | Download Citation

Abstract

Malignant melanoma is a highly aggressive form of skin cancer responsible for the majority of skin cancer-related deaths. Recent insight into the heterogeneous nature of melanoma suggests more personalised treatments may be necessary to overcome drug resistance and improve patient care. To this end, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified. In this study, we applied multiplex phosphoproteomic profiling across a panel of 24 melanoma cell lines with different disease-relevant mutations, to predict responsiveness to MEK inhibitor trametinib. Supported by multivariate statistical analysis and multidimensional pattern recognition algorithms, the responsiveness of individual cell lines to trametinib could be predicted with high accuracy (83% correct predictions), independent of mutation status. We also successfully employed this approach to case specifically predict whether individual melanoma cell lines could be sensitised to trametinib. Our predictions identified that combining MEK inhibition with selective targeting of c-JUN and/or FAK, using siRNA-based depletion or pharmacological inhibitors, sensitised resistant cell lines and significantly enhanced treatment efficacy. Our study indicates that multiplex proteomic analyses coupled with pattern recognition approaches could assist in personalising trametinib-based treatment decisions in the future.

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Edited by G Melino

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Acknowledgements

LGA, MR, DK, PA and TS receive funding through the EU Horizon 2020 MEL-PLEX program (grant agreement #642295). LGA also receives funding through the Horizon 2020 SyMBioSys program (grant agreement #675585). LGA and VP also receives funding from European Union and Greek National Funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate (project code:T1EDK-03532). MR also receives support from the German Research Foundation (FOR2036; MO 3226/1–1) and the Health Research Board Ireland (HRA POR 2013 245). DK also receives funding from Federal Ministry of Education and Research (BMBF: FKZ 031A423A, Melanoma Sensitivity). TS also receives funding from the Luxembourg National Research Fund (FNR: BMBF/BM/7643621, Melanoma Sensitivity). The authors wish to thank Prof Thomas Brunner (University of Konstanz, Germany) for helpful advice.

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Author notes

  1. These authors contributed equally: Markus Rehm, Leonidas G. Alexopoulos

Affiliations

  1. Life Sciences Research Unit, University of Luxembourg, Belvaux, Luxembourg

    • Jan Rožanc
    •  & Thomas Sauter
  2. ProtATonce Ltd, Science Park Demokritos, Athens, Greece

    • Jan Rožanc
    • , Asier Antoranz
    • , Vaia Pliaka
    •  & Leonidas G. Alexopoulos
  3. Department of Mechanical Engineering, National Technical University of Athens, Athens, Greece

    • Theodore Sakellaropoulos
    • , Asier Antoranz
    •  & Leonidas G. Alexopoulos
  4. Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany

    • Cristiano Guttà
    • , Biswajit Podder
    • , Vesna Vetma
    •  & Markus Rehm
  5. Laboratory for Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

    • Nicole Rufo
    •  & Patrizia Agostinis
  6. Experimental Dermatology, Department of Dermatology, Technical University Dresden, Dresden, Germany

    • Dagmar Kulms
  7. Center for Regenerative Therapies, Technical University Dresden, Dresden, Germany

    • Dagmar Kulms
  8. Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany

    • Markus Rehm
  9. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland

    • Markus Rehm
  10. Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland

    • Markus Rehm

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Leonidas G. Alexopoulos.

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DOI

https://doi.org/10.1038/s41418-018-0210-8