Betancourt, L. | bioRxiv Science

bioRxiv2024

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts

While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making. O_FIG O_LINKSMALLFIG WIDTH=164 HEIGHT=200 SRC="FIGDIR/small/592032v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@754668org.highwire.dtl.DTLVardef@1616263org.highwire.dtl.DTLVardef@827009org.highwire.dtl.DTLVardef@1899ba7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Proteogenomic Characterization Reveals Therapeutic Opportunities Related to Mitochondrial Function in Melanoma

The dynamics of more than 1900 mitochondrial proteins was explored through quantitative proteomics in 151 melanoma-related tissue samples of both surgical and autopsy origin. Dysregulation of mitochondrial pathways in primary tumors, metastases, and peritumoral tissues was correlated with age and survival of patients, as well as with tumor cell proliferation and the BRAF mutation status of the tumors. The outlined proteomic landscape confirmed the central role of a pathologically upregulated mitochondrial translation machinery and oxidative phosphorylation (OXPHOS) in the development, proliferation, and progression of melanomas. Our results from different melanoma cell lines confirmed our findings and we could document that treatments with selected OXPHOS inhibitors and antibiotics successfully impaired tumor cell proliferation. In addition, we provided proteomic evidence on the mechanism-of-action of the different treatments. These observations could contribute to the development of therapeutic approaches targeting the mitochondrial pathology in melanoma. TOC figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/513481v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@11f21e2org.highwire.dtl.DTLVardef@e98c64org.highwire.dtl.DTLVardef@100145forg.highwire.dtl.DTLVardef@399284_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMitochondrial proteome landscape outlined in 151 melanoma-related samples C_LIO_LIMitochondrial Translation and OXPHOS impact disease severity and survival C_LIO_LIBRAF V600E mutation correlates with upregulation of mitochondrial energy production C_LIO_LITargeting the mitochondrial OXPHOS and ribosomes impairs tumor cell proliferation C_LIO_LITherapeutic opportunities complementary to the standard of care are proposed C_LI In briefMitochondrial proteome profiling of melanomas reveals dysregulation in major metabolic pathways, suggesting a central role of the mitochondria within the development and progression of melanoma. Targeting mitochondrial pathways has the potential to impact the course of the disease, which provides opportunities for complementary drug interventions.

cancer biology↗