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

B Shannan; J Matschke; H Chauvistré; F Vogel; D Klein; F Meier; D Westphal; J Bruns; R Rauschenberg; J Utikal; A Forschner; C Berking; P Terheyden; E Dabrowski; R Gutzmer; D Rafei-Shamsabadi; F Meiss; L Heinzerling; L Zimmer; Elisabeth Livingstone; Renáta Váraljai; A Hoewner; S Horn; J Klode; M Stuschke; B Scheffler; A Marchetto; G Sannino; T G P Grünewald; D Schadendorf; V Jendrossek; A Roesch

doi:10.1016/j.ejca.2018.12.024

Sequence-dependent cross-resistance of combined radiotherapy plus BRAF^V600E inhibition in melanoma

Eur J Cancer. 2019 Mar:109:137-153. doi: 10.1016/j.ejca.2018.12.024. Epub 2019 Feb 2.

Authors

B Shannan¹, J Matschke², H Chauvistré¹, F Vogel¹, D Klein², F Meier³, D Westphal³, J Bruns³, R Rauschenberg³, J Utikal⁴, A Forschner⁵, C Berking⁶, P Terheyden⁷, E Dabrowski⁸, R Gutzmer⁹, D Rafei-Shamsabadi¹⁰, F Meiss¹⁰, L Heinzerling¹¹, L Zimmer¹, Elisabeth Livingstone¹, Renáta Váraljai¹, A Hoewner¹, S Horn¹, J Klode¹, M Stuschke¹², B Scheffler¹, A Marchetto¹³, G Sannino¹³, T G P Grünewald¹⁴, D Schadendorf¹, V Jendrossek², A Roesch¹⁵

Affiliations

¹ Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Germany.
² Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Germany.
³ Skin Cancer Center National Center for Tumor Diseases, Department of Dermatology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany.
⁴ Skin Cancer Unit German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
⁵ Department of Dermatology, Center for Dermatooncology, University Hospital Tübingen, Germany.
⁶ Department of Dermatology and Allergy, University Hospital of Munich, Munich, Germany.
⁷ Department of Dermatology, University of Luebeck, Luebeck, Germany.
⁸ Department of Dermatology, Klinikum Ludwigshafen, Ludwigshafen, Germany.
⁹ Skin Cancer Centre, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
¹⁰ Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
¹¹ Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
¹² Department of Radiotherapy, West German Cancer Center, University Hospital, University of Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Essen, Germany.
¹³ Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Germany.
¹⁴ Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK) University of Duisburg-Essen, Germany. Electronic address: alexander.roesch@uk-essen.de.

PMID: 30721788
DOI: 10.1016/j.ejca.2018.12.024

Abstract

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^V600E 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^high 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.

Keywords: Cross-resistance; JARID1B/KDM5B; Melanoma; Radiotherapy; Repopulation; Resistance; Slow-cycling cells; Targeted therapy; Therapy sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Apoptosis
Brain Neoplasms / genetics
Brain Neoplasms / secondary
Brain Neoplasms / therapy*
Cell Cycle
Cell Movement
Cell Proliferation
Chemoradiotherapy
Drug Resistance, Neoplasm*
Female
Follow-Up Studies
Humans
MAP Kinase Signaling System / drug effects
Male
Melanoma / genetics
Melanoma / pathology
Melanoma / therapy*
Middle Aged
Mutation
Prognosis
Protein Kinase Inhibitors / therapeutic use*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / genetics
Radiation Tolerance*
Radiotherapy*
Retrospective Studies
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Protein Kinase Inhibitors
BRAF protein, human
Proto-Oncogene Proteins B-raf