title: Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation.
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.
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. Electronic address: hkim@sbmri.org.
authors.forename: Hyungsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Cambridge, MA 02114, USA.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Department of Dermatology, University Hospital of Zürich and University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Levesque
authors.affiliation: Departments of Genomic Medicine and Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Melanoma Research Center, Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Brill
authors.affiliation: Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ally
authors.initials: A
authors.lastname: Perlina
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Cambridge, MA 02114, USA.
authors.forename: Adriano
authors.initials: A
authors.lastname: Piris
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Tongwu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.affiliation: Melanoma Research Center, Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Meenhard M
authors.initials: MM
authors.lastname: Herlyn
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.affiliation: Departments of Genomic Medicine and Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Department of Dermatology, University Hospital of Zürich and University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Cambridge, MA 02114, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. Electronic address: ronai@sbmri.org.
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053613:Janus Kinase 1 / Q000378:metabolism*; D013058:Mass Spectrometry; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; C551868:RNF125 protein, human; D044767:Ubiquitin-Protein Ligases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf