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

Background 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 emerg...

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Bibliographic Details
Published in:Journal of cancer research and clinical oncology 2023-02, Vol.149 (2), p.669-682
Main Authors: Torlot, Lucien, Jarzab, Anna, Albert, Johanna, Pók-Udvari, Ágnes, Stahler, Arndt, Holch, Julian Walter, Gerlinger, Marco, Heinemann, Volker, Klauschen, Frederick, Kirchner, Thomas, Kumbrink, Jörg, Küster, Bernhard, Jung, Andreas
Format: Article
Language:English
Subjects:
Antineoplastic Agents - therapeutic use
Cancer Research
Cell Line, Tumor
Cell migration
Cetuximab - pharmacology
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Drug Resistance, Neoplasm - genetics
EphA2 protein
ErbB Receptors - genetics
Hematology
Humans
Internal Medicine
Medicine
Medicine & Public Health
Metastases
Monoclonal antibodies
Mutation
Oncology
Original Article – Cancer Research
Original – Cancer Research
Precision medicine
Proteomics
Proto-Oncogene Proteins p21(ras) - genetics
RNA-mediated interference
Targeted cancer therapy
Therapeutic targets
Tumor cell lines
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Summary:Background 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. Methods To uncover potential targets for second-line targeted therapies, we used mass-spectrometric proteomics to shed light on kinome reprogramming in an established cellular model of acquired, KRAS -associated CET resistance. Results This CET resistance was reflected by significant changes in the kinome, most of them individual to each cell line. Interestingly, all investigated resistant cell lines displayed upregulation of the Ephrin type-A receptor 2 (EPHA2), a well-known driver of traits of progression. Expectedly resistant cell lines displayed increased migration ( p  
ISSN:0171-5216
1432-1335
DOI:10.1007/s00432-022-04416-0