Dataset Information

Proteomics uncover EPHA2 in cetuximab resistant colorectal cancer cell lines as a potential novel therapeutic target

ABSTRACT: In metastatic colorectal cancer (mCRC), primary and acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), were shown to be frequently caused by activating alterations in RAS genes (KRAS or NRAS). To this day no efficient second-line treatment options have emerged to treat mCRC upon emergence of acquired KRAS alterations. In order to uncover potential targets for second-line targeted therapies, we used mass spectrometric proteomics to shed light on kinome reprogramming in an established model of acquired, KRAS associated CET resistance. This CET resistance was reflected by significant changes in the kinome, most of them individual to each cell line. Interestingly a common theme in all investigated resistant cell lines was the upregulation of the Ephrin type-A receptor 2 (EPHA2), a well-known driver of cell migration. Expectedly resistant cell lines displayed increased migration (p<0.01) that was significantly reduced by targeting the EPHA2 signalling axis using RNA interference (p<0.001), ephrin-A1 stimulation (p<0.001), dasatinib (p<0.01) or anti-EPHA2 antibody treatment (p<0.001), identifying it as an actionable target in CET resistant mCRC. These results highlight EPHA2 and its role in KRAS mutated acquired CET resistance in mCRC and identify it as a potential target for the development of future precision medicine therapies.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Colon

DISEASE(S): Colon Cancer

SUBMITTER: Anna Jarzab

LAB HEAD: Bernhard Kuster

PROVIDER: PXD022072 | Pride | 2023-03-10

REPOSITORIES: Pride

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			Action	DRS
	02500_GA10_P027996_S00_T25_R1.raw	Raw
	02500_GA1_P027995_S00_T01_R1.raw	Raw
	02500_GA2_P027995_S00_T09_R1.raw	Raw
	02500_GA3_P027995_S00_T17_R1.raw	Raw
	02500_GA4_P027995_S00_T25_R1.raw	Raw

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Proteomics uncover EPHA2 as a potential novel therapeutic target in colorectal cancer cell lines with acquired cetuximab resistance.

Torlot Lucien L Jarzab Anna A Albert Johanna J Pók-Udvari Ágnes Á Stahler Arndt A Holch Julian Walter JW Gerlinger Marco M Heinemann Volker V Klauschen Frederick F Kirchner Thomas T Kumbrink Jörg J Küster Bernhard B Jung Andreas A

Journal of cancer research and clinical oncology 20221119 2

<h4>Background</h4>In metastatic colorectal cancer (mCRC), acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), was shown to be frequently caused by activating alterations in the RAS genes KRAS or NRAS. To this day, no efficient follow-up treatment option has emerged to treat mCRC in such a setting of resistance.<h4>Methods</h4>To uncover potential targets for second-line targeted therapies, we used mass-spectrometric proteomics to shed light on kinome r ...[more]

PMID: 36401637

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