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Proteomic identification of a marker signature for MAPK i resistance in melanoma
Author(s) -
Paulitschke Verena,
Eichhoff Ossia,
Gerner Christopher,
Paulitschke Philipp,
Bileck Andrea,
Mohr Thomas,
Cheng Phil F,
Leitner Alexander,
Guenova Emmanuella,
Saulite Ieva,
Freiberger Sandra N,
Irmisch Anja,
Knapp Bernhard,
Zila Nina,
Chatziisaak TheodoraPagona,
Stephan Jürgen,
Mangana Joanna,
Kunstfeld Rainer,
Pehamberger Hubert,
Aebersold Ruedi,
Dummer Reinhard,
Levesque Mitchell P
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695874
Subject(s) - biology , identification (biology) , signature (topology) , proteomics , microbiology and biotechnology , computational biology , genetics , gene , botany , geometry , mathematics
MAPK inhibitors ( MAPK i) show outstanding clinical response rates in melanoma patients harbouring BRAF mutations, but resistance is common. The ability of melanoma cells to switch from melanocytic to mesenchymal phenotypes appears to be associated with therapeutic resistance. High‐throughput, subcellular proteome analyses and RNAseq on two panels of primary melanoma cells that were either sensitive or resistant to MAPK i revealed that only 15 proteins were sufficient to distinguish between these phenotypes. The two proteins with the highest discriminatory power were PTRF and IGFBP 7, which were both highly upregulated in the mesenchymal‐resistant cells. Proteomic analysis of CRISPR /Cas‐derived PTRF knockouts revealed targets involved in lysosomal activation, endocytosis, pH regulation, EMT , TGF β signalling and cell migration and adhesion, as well as a significantly reduced invasive index and ability to form spheres in 3D culture. Overexpression of PTRF led to MAPK i resistance, increased cell adhesion and sphere formation. In addition, immunohistochemistry of patient samples showed that PTRF expression levels were a significant biomarker of poor progression‐free survival, and IGFBP 7 levels in patient sera were shown to be higher after relapse.