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Cell Rep. 2015 Jun 9;11(9):1458-73. doi: 10.1016/j.celrep.2015.04.049. Epub 2015 May 28.

Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation.

Author information

1
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. Electronic address: hkim@sbmri.org.
2
Massachusetts General Hospital, Harvard Medical School, Cambridge, MA 02114, USA.
3
Department of Dermatology, University Hospital of Zürich and University of Zürich, 8091 Zürich, Switzerland.
4
Departments of Genomic Medicine and Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
6
Melanoma Research Center, Wistar Institute, Philadelphia, PA 19104, USA.
7
Weizmann Institute, Rehovot 76100, Israel.
8
QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
9
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
10
Department of Dermatology, Yale School of Medicine, New Haven, CT 06520, USA.
11
Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. Electronic address: ronai@sbmri.org.

Abstract

Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription. Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases (RTKs), including EGFR. Notably, RNF125 altered RTK expression through JAK1, which we identified as an RNF125 substrate. RNF125 bound to and ubiquitinated JAK1, prompting its degradation and suppressing RTK expression. Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression, as shown in culture and in in vivo xenografts. Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression.

PMID:
26027934
PMCID:
PMC4681438
DOI:
10.1016/j.celrep.2015.04.049
[Indexed for MEDLINE]
Free PMC Article

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