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

Abstract

SUMMARYDespite 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.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…4a). This 'MITF low ' phenotype is also potentially amenable to targeted intervention, as many MITF outputs are under the control of JAK signalling and could, therefore, be amendable to JAK-inhibitor therapy 135 .…”

Regulation of HDAC2-PDX1 by RNF125 defines pancreatic cancer development

“…To identify UBLs that contribute to the etiology of PDA, we queried the TCGA database for UBLs differentially expressed in cancer, including melanoma 27,30 , ovarian cancer 31 , breast cancer [32][33][34] , colorectal cancer 35,36 , lung cancer 37 , and head and neck cancer 36,38 . Of the UBLs that were altered in pancreatic cancer ( Fig S1A) we selected UBLs whose expression may be linked with survival.…”

“…Mouse: #1; TRCN0000026039, #2; TRCN0000025966), and HDAC2 (Human: #1; TRCN0000004819, #2; TRCN0000004820.Mouse: #1; TRCN0000039397, #2: TRCN0000039395) were purchased from La Jolla Institute for Allergy and Immunology. FLAG-tagged RNF125 wild type (WT) and RING mutant (RM) vectors was previously described27 . The HDAC2 expression vector was constructed in pLX304-V5 Gateway vector from pDONR223-HDAC2 (DNASU #HsCD00005288).…”

Chemotherapy resistance mechanisms in advanced skin cancer

“…Recently deregulation of Janus kinase 1 (JAK1) was identified in melanoma resistant to BRAF inhibitors, and to overcome such resistance the use of combination therapy was suggested, which may improve the durability of the response to BRAF inhibitors. 77 …”