Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma

Journal article

Publication Details

Author(s): Shannan B, Matschke J, Chauvistre H, Vogel F, Klein D, Meier F, Westphal D, Bruns J, Rauschenberg R, Utikal J, Forschner A, Berking C, Terheyden P, Dabrowski E, Gutzmer R, Rafei-Shamsabadi D, Meiss F, Heinzerling L, Zimmer L, Livingstone E, Varaljai R, Hoewner A, Horn S, Klode J, Stuschke M, Scheffler B, Marchetto A, Sannino G, Gruenewald TGP, Schadendorf D, Jendrossek , Roesch A
Journal: European journal of cancer
Publication year: 2019
Volume: 109
Pages range: 137-153
ISSN: 0959-8049


Introduction: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. Methods & results: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAF
inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor–pretreated compared with MAPK-inhibitor–naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1B
cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. Conclusion: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

FAU Authors / FAU Editors

Heinzerling, Lucie Prof. Dr.

External institutions with authors

Albert-Ludwigs-Universität Freiburg
Deutsches Krebsforschungszentrum (DKFZ)
Klinikum der Stadt Ludwigshafen am Rhein gGmbH
Klinikum der Universität München (Großhadern und Innenstadt)
Ludwig-Maximilians-Universität (LMU)
Medizinische Hochschule Hannover (MHH) / Hannover Medical School
Technische Universität Dresden
Universität Duisburg-Essen (UDE)
Universitätsklinikum Tübingen
Universität zu Lübeck

How to cite

Shannan, B., Matschke, J., Chauvistre, H., Vogel, F., Klein, D., Meier, F.,... Roesch, A. (2019). Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma. European journal of cancer, 109, 137-153.

Shannan, B., et al. "Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma." European journal of cancer 109 (2019): 137-153.


Last updated on 2019-04-05 at 09:08