TP53 has been proved to be associated with cytotoxic T-cell induced apoptosis, however, the association between TP53 and the benefit of immunotherapy in melanoma has not been studied.,In the present study, we examined the relationship between TP53 mutation and response to CTLA-4 blockade in metastatic melanoma by analyzing the data from one public cohort consisting of 110 patients with metastatic melanoma.,The sequencing, mRNA and survival data of 368 patients with skin melanoma from The Cancer Genome Atlas (TCGA) was used to explore the underlying mechanism.,TP53 mutation was associated with significant poorer progression-free survival (HR, 2.25; 95% CI, 1.15-4.37; P = 0.014), poorer overall survival (HR, 2.05; 95% CI, 1.02-4.13; P = 0.040) and trend of poorer response (OR, 0.20; 95% CI, 0.02-1.62; P = 0.131).,The correlations were significant in multivariate analysis including lactate dehydrogenase, tumor mutational burden and tumor stage (P < 0.05).,In TCGA, no association was observed between TP53 mutation and survival (P = 0.55).,The mRNA expression of FAS was lower in patients with TP53 mutation than TP53 wild-type.,Our findings suggest that TP53 mutation is a potential negative predictor of metastatic melanoma treated with CTLA-4 blockade.,•TP53 mutation is associated with poorer outcomes in patients with metastatic melanoma receiving anti-CTLA-4 treatment.,•The mRNA expression of FAS was lower in patients with TP53 mutation than TP53 wild-type.,•TP53 is a potential negative predictor of metastatic melanoma treated with CTLA-4 blockade.,TP53 mutation is associated with poorer outcomes in patients with metastatic melanoma receiving anti-CTLA-4 treatment.,The mRNA expression of FAS was lower in patients with TP53 mutation than TP53 wild-type.,TP53 is a potential negative predictor of metastatic melanoma treated with CTLA-4 blockade.,Immune checkpoint blockades by enhancing the anti-tumor activity of immune system have been standard treatment for several advanced tumors, however, only a subset of patients can benefit from them.,In this study, we find patients with melanoma harboring TP53 mutation show poorer survival outcome and response of anti-CTLA-4 treatment.,The mRNA expression of FAS is lower in patients with TP53 mutation, suggesting that TP53 down-regulates the expression of FAS and impede cytotoxic T-cell induced apoptosis in melanoma.,These results suggest that TP53 mutation may serve as a negative predictor of anti-CTLA-4 treatment in melanoma.
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.