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Proteomics identifies markers of MAPKi resistance offering new therapeutic strategies in melanoma- Cytoplasmic (cyt), nuclear (ne) and secreted (sn) proteins of MAPKi sensitive melanoma cells

ABSTRACT: MAPK inhibitors (MAPKi) show outstanding clinical response rates in melanoma patients harbouring BRAF mutations, but resistance is common. High-throughput, subcellular proteome analyses at two different MS laboratories and RNA-seq on two panels of primary melanoma cells that were either sensitive or MAPKi resistant, revealed that only fifteen proteins were sufficient to discriminate between resistant and sensitive cells. The two proteins with the highest discriminatory power were PTRF and IGFBP7, both highly upregulated in the resistant cells. They were associated with epithelial-mesenchymal transition (EMT) and are mechanistically linked. Knock-out of PTRF revealed targets involved in lysosomal activation, endocytosis, pH regulation, EMT, TGFbeta signalling and cell migration and adhesion. In addition, immunohistochemistry on patient samples showed that PTRF and IGFBP7 expression levels were significant biomarkers of poor progression free survival under MAPKi treatment. A drug screen of MAPKi resistant cells using a 960-compound kinase modulator library identified two lead compounds that were effective in targeting MAPKi resistant cells.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Skin

DISEASE(S): Melanoma

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD005432 | Pride | 2019-07-23

REPOSITORIES: Pride

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			Action	DRS
	MM000921_MAPKi_sensitive_cyt_1.mgf	Mgf
	MM000921_MAPKi_sensitive_cyt_1.mzid.gz	Mzid
	MM000921_MAPKi_sensitive_cyt_1.pride.mgf.gz	Mgf
	MM000921_MAPKi_sensitive_cyt_1.pride.mztab.gz	Mztab
	MM000921_MAPKi_sensitive_cyt_1.raw	Raw

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Proteomics identifies markers of MAPKi resistance offering new therapeutic strategies in melanoma- Cytoplasmic (cyt), nuclear (ne) and secreted (sn) proteins of BRAFi resistant melanoma cells

Project description:MAPK inhibitors (MAPKi) show outstanding clinical response rates in melanoma patients harbouring BRAF mutations, but resistance is common. High-throughput, subcellular proteome analyses at two different MS laboratories and RNA-seq on two panels of primary melanoma cells that were either sensitive or MAPKi resistant, revealed that only fifteen proteins were sufficient to discriminate between resistant and sensitive cells. The two proteins with the highest discriminatory power were PTRF and IGFBP7, both highly upregulated in the resistant cells. They were associated with epithelial-mesenchymal transition (EMT) and are mechanistically linked. Knock-out of PTRF revealed targets involved in lysosomal activation, endocytosis, pH regulation, EMT, TGFbeta signalling and cell migration and adhesion. In addition, immunohistochemistry on patient samples showed that PTRF and IGFBP7 expression levels were significant biomarkers of poor progression free survival under MAPKi treatment. A drug screen of MAPKi resistant cells using a 960-compound kinase modulator library identified two lead compounds that were effective in targeting MAPKi resistant cells.

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