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

Lucien Torlot, Anna Jarzab, Johanna Albert, Ágnes Pók-Udvari, Arndt Stahler, Julian Walter Holch, Marco Gerlinger, Volker Heinemann, Frederick Klauschen, Thomas Kirchner, Jörg Kumbrink, Bernhard Küster, Andreas Jung

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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 < 0.01) that was significantly reduced by targeting the EPHA2 signalling axis using RNA interference (RNAi) (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 mCRC with acquired CET resistance. Conclusion: These results highlight EPHA2 and its role in mCRC with KRAS-gene mutated acquired CET resistance and support its use as a potential actionable target for the development of future precision medicine therapies.

Original languageEnglish
Pages (from-to)669-682
Number of pages14
JournalJournal of Cancer Research and Clinical Oncology
Volume149
Issue number2
DOIs
StatePublished - Feb 2023

Keywords

  • Cetuximab resistance
  • Colorectal cancer
  • EPHA2
  • Molecular oncology
  • Proteomics

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