- •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.
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.
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.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to European Journal of Cancer
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Melanoma.Nat Rev Dis Primers. 2015; 1: 15003
- Tumor heterogeneity and plasticity as elusive drivers for resistance to MAPK pathway inhibition in melanoma.Oncogene. 2015; 34: 2951-2957
- Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases.Br J Canc. 2017; 116: 1558-1563
- Outcomes in melanoma patients treated with BRAF/MEK-Directed therapy or immune checkpoint inhibition stratified by clinical trial versus standard of care.Oncology. 2017; 93: 164-176
- Combination controversies: checkpoint inhibition alone or in combination for the treatment of melanoma?.Oncology (Williston Park). 2018; 32: 228-234
- Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: a network meta-analysis.Cancer Treat Rev. 2017; 54: 34-42
- Molecular insights into melanoma brain metastases.Cancer. 2017; 123: 2163-2175
- BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy.Onco Targets Ther. 2016; 9: 7149-7159
- Survival of patients with melanoma brain metastasis treated with stereotactic radiosurgery and active systemic drug therapies.Eur J Cancer. 2017; 75: 169-178
- Radiosurgery/stereotactic radiotherapy in combination with immunotherapy and targeted agents for melanoma brain metastases.Expert Rev Anticancer Ther. 2017; 17: 347-356
- Non-genomic and immune evolution of melanoma acquiring MAPKi resistance.Cell. 2015; 162: 1271-1285
- Exploiting drug addiction mechanisms to select against MAPKi-resistant melanoma.Cancer Discov. 2018; 8: 74-93
- The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.Cancer Discov. 2014; 4: 94-109
- Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma.Clin Cancer Res. 2018; 24: 1260-1270
- A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth.Cell. 2010; 141: 583-594
- Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells.Cancer Cell. 2013; 23: 811-825
- JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells.Oncotarget. 2015; 6: 12723-12739
- Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma.Proc Natl Acad Sci U S A. 2013; 110: 18226-18231
- Jumonji inhibitors overcome radioresistance in cancer through changes in H3K4 methylation at double-strand breaks.Cell Rep. 2018; 25: 1040-10450 e5
- Targeted inhibition of glutamine-dependent glutathione metabolism overcomes death resistance induced by chronic cycling hypoxia.Antioxidants Redox Signal. 2016; 25: 89-107
- DNA damage checkpoint control in cells exposed to ionizing radiation.Oncogene. 2003; 22: 5834-5847
- ATM, a central controller of cellular responses to DNA damage.Cell Death Differ. 2001; 8: 1052-1065
- Increased G2 delay in radiation-resistant cells obtained by transformation of primary rat embryo cells with the oncogenes H-ras and v-myc.Radiat Res. 1991; 125: 283-287
- Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma.Nature. 2016; 539: 309-313
- H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence.Proc Natl Acad Sci U S A. 2012; 109: 8971-8976
- Data mining the cancer genome Atlas in the era of precision cancer medicine.Swiss Med Wkly. 2015; 145: w14183
- The cancer genome atlas pan-cancer analysis project.Nat Genet. 2013; 45: 1113-1120
- Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.Proc Natl Acad Sci U S A. 2005; 102: 15545-15550
- PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.Nat Genet. 2003; 34: 267-273
- Re-expression of the retinoblastoma-binding protein 2-homolog 1 reveals tumor-suppressive functions in highly metastatic melanoma cells.J Invest Dermatol. 2006; 126: 1850-1859
- Radiotherapy with BRAF inhibitor therapy for melanoma: progress and possibilities.Future Oncol. 2016; 12: 95-106
- Trametinib radiosensitises RAS- and BRAF-mutated melanoma by perturbing cell cycle and inducing senescence.Radiother Oncol. 2015; 117: 364-375
- Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032.Radiother Oncol. 2011; 98: 394-399
- Silencing JARID1B suppresses oncogenicity, stemness and increases radiation sensitivity in human oral carcinoma.Cancer Lett. 2015; 368: 36-45
- Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial.Lancet Oncol. 2017; 18: 863-873
- JARID1B enables transit between distinct states of the stem-like cell population in oral cancers.Cancer Res. 2016; 76: 5538-5549
- The histone demethylase KDM5b/JARID1b plays a role in cell fate decisions by blocking terminal differentiation.Mol Cell Biol. 2008; 28: 5312-5327
- PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation.Mol Cell. 2007; 25: 801-812
- Demethylation of histone H3K36 and H3K9 by Rph1: a vestige of an H3K9 methylation system in Saccharomyces cerevisiae?.Mol Cell Biol. 2007; 27: 3951-3961
- RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3.Cell. 2007; 128: 1063-1076
- The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases.Cell. 2007; 128: 1077-1088
- Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos.Nature. 2016; 537: 558-562
- Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB.Proc Natl Acad Sci U S A. 1993; 90: 393-397
- Adenovirus infection enhances killing of melanoma cells by a mitotoxin.Cancer Res. 1997; 57: 1873-1876
- Single-vector inducible lentiviral RNAi system for oncology target validation.Cell Cycle. 2009; 8: 498-504
- Cracking the system: melanoma complexity demands new therapeutic approaches.Pigment Cell Melanoma Res. 2009; 22: 4-5
Published online: February 02, 2019
Accepted: December 29, 2018
Received in revised form: December 22, 2018
Received: November 21, 2018
© 2019 Elsevier Ltd. All rights reserved.