Proteomics-based insights into mitogen-activated protein kinase inhibitor resistance of cerebral melanoma metastases

ABSTRACT: Background MAP kinase inhibitor (MAPKi) therapy for BRAF mutated melanoma is characterized by high response rates but also development of drug resistance within a median progression-free survival (PFS) of 9 to 12 months. Understanding mechanisms of resistance and identifying effective therapeutic alternatives is one of the most important scientific challenges in melanoma. Using proteomics, we want to specifically gain insight into the pathophysiological process of cerebral metastases. Methods Cerebral metastases from melanoma patients were prepared for MS analysis by tryptic digestion. Mass spectrometric analysis was performed on a QExactive HF hybrid quadrupole-orbitrap mass spectrometer, equipped with a nanospray ion source, coupled with a nano HPLC system. Results In this pilot study, we were able to identify 5,977 proteins by LC-MS analysis. Samples were classified into good and poor responders based on PFS. By evaluating these proteomic profiles according to gene ontology (GO) terms, KEGG pathways and gene set enrichment analysis (GSEA), we could characterize differences between the two distinct groups. We further detected an EMT signature, V-type proton ATPases, calcium ion binding proteins, eukaryotic translation initiation factors, cell adhesion proteins and several transporter and exchanger proteins to be significantly up-regulated in poor responding patients, whereas good responders showed an immune-activation and involvement of extracellular matrix structural constituents, among other features. Subsequently we identified the most class-discriminating proteins based on nearest shrunken centroids. Conclusions Using proteomics helped to identify already known extra-cerebral resistance mechanisms in the cerebral metastases and further discovered possible brain specific mechanisms of drug efflux, which might serve as interesting targets, especially for treatment of these types of metastases or as predictive marker.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Christopher Gerner  

PROVIDER: MSV000082948 | MassIVE |

SECONDARY ACCESSION(S): PXD007592

REPOSITORIES: MassIVE