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| The EMBO journal. 2019 Jun 26. doi: 10.15252/embj.201695874 |
| Proteomic identification of a marker signature for MAPKi resistance in melanoma. |
| Paulitschke V1, Eichhoff O2, Gerner C3, Paulitschke P4, Bileck A5, Mohr T6, Cheng PF7, Leitner A8, Guenova E9, Saulite I10, Freiberger SN11, Irmisch A12, Knapp B13, Zila N14, Chatziisaak TP15, Stephan J16, Mangana J17, Kunstfeld R18, Pehamberger H19, Aebersold R20, Dummer R21, Levesque MP22 |
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Abstract MAPK inhibitors (MAPKi) 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 MAPKi revealed that only 15 proteins were sufficient to distinguish between these phenotypes. The two proteins with the highest discriminatory power were PTRF and IGFBP7, 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, TGFβ 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 MAPKi 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 IGFBP7 levels in patient sera were shown to be higher after relapse. |
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© 2019 The Authors. |
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KEYWORDS: BRAF , PTRF , mass spectrometry, melanoma, resistance |
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Publikations ID: 31267558 Quelle: öffnen |
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