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

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

  • J Cancer Res Clin Oncol. 2022 Nov 19. doi: 10.1007/s00432-022-04416-0.
Lucien Torlot 1 2,  Anna Jarzab 3,  Johanna Albert 1,  Ágnes Pók-Udvari 1,  Arndt Stahler 4 5,  Julian Walter Holch 2 6 7,  Marco Gerlinger 8 9 10,  Volker Heinemann 2 6 7,  Frederick Klauschen 1 2 7,  Thomas Kirchner 1 2 7,  Jörg Kumbrink 1 2 7,  Bernhard Küster 2 3,  Andreas Jung 11 12 13
Affiliations

Affiliations

  • 1 Institute of Pathology, Ludwig-Maximilians-University (LMU), Munich, Germany.
  • 2 German Cancer Consortium (DKTK), Heidelberg, Munich Site, Germany.
  • 3 Chair or Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.
  • 4 Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • 5 German Cancer Consortium (DKTK), Heidelberg, Berlin, Germany.
  • 6 Department of Medicine III, LMU Hospital, Munich, Germany.
  • 7 Comprehensive Cancer Center Munich (CCCM), LMU Hospital, Munich, Germany.
  • 8 Translational Oncogenomics Lab, The Institute of Cancer Research, London, UK.
  • 9 Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 10 Gastrointestinal Cancer Unit, St Bartholomew's Hospital, London, UK.
  • 11 Institute of Pathology, Ludwig-Maximilians-University (LMU), Munich, Germany. [email protected].
  • 12 German Cancer Consortium (DKTK), Heidelberg, Munich Site, Germany. [email protected].
  • 13 Comprehensive Cancer Center Munich (CCCM), LMU Hospital, Munich, Germany. [email protected].
PMID: 36401637 DOI: 10.1007/s00432-022-04416-0
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.

Keywords

Cetuximab resistance; Colorectal cancer; EPHA2; Molecular oncology; Proteomics.

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