Highlights
- •Higher rate of tumour relapse under upfront mitogen-activated protein kinase (MAPK)-inhibition as compared with upfront radiation.
- •JARID1B/KDM5Bhigh cells appeared more often under upfront MAPK-inhibition as compared with upfront radiation.
- •JARID1B/KDM5B may represent a novel therapy-overarching (cross-) resistance marker.
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 BRAFV600E 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. JARID1Bhigh 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
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Article info
Publication history
Published online: February 02, 2019
Accepted:
December 29,
2018
Received in revised form:
December 22,
2018
Received:
November 21,
2018
Identification
Copyright
© 2019 Elsevier Ltd. All rights reserved.
