EphA2 receptor activation with ephrin-A1 ligand restores cetuximab efficacy in NRAS-mutant colorectal cancer cells

  • Authors:
    • Elisabet Cuyàs
    • Bernardo Queralt
    • Begoña Martin-Castillo
    • Joaquim Bosch-Barrera
    • Javier A. Menendez
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  • Published online on: May 30, 2017     https://doi.org/10.3892/or.2017.5682
  • Pages: 263-270
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Abstract

Patients with wild-type KRAS metastatic colorectal cancer (mCRC) that harbors NRAS activating mutations do not benefit from anti-EGFR therapies. Very little is known about oncogenic NRAS signaling driving mCRC unresponsiveness to the EGFR-directed antibody cetuximab. Using a system of paired NRAS-mutant and wild-type isogenic mCRC cell lines to explore signaling pathways engaged by the common oncogenic NRAS Q61K variant upon challenge with cetuximab, we uncovered an unexpected mechanism of resistance to cetuximab involving dysregulation of the ephrin-A1/EphA2 signaling axis. Parental NRAS+/+ cells, but not NRASQ61K/+ cells, activated the ephrin receptor ephA1 in response to cetuximab treatment. Moreover, whereas cetuximab treatment significantly downregulated EPHA2 gene expression in NRAS+/+ cells, EPHA2 expression in NRASQ61K/+ cells was refractory to cetuximab. Remarkably, pharmacologically mimicked ephrin-A1 engagement to ephA2 converted NRAS-mutant into RAS wild-type mCRC cells in terms of cetuximab efficacy. Accordingly, activation of the ephA2 receptor by bioactive recombinant human ephrin-A1/Fc-fusion protein suppressed the cetuximab-unresponsive hyperactivation of MAPK and AKT and fully restored cetuximab activity in NRAS-mutant colorectal cells. Collectively, these findings reveal that the clinical benefit of cetuximab in mCRC might necessarily involve the suppression of the ligandless oncogenic signaling of the ephA2 receptor. Hence, ligand-dependent tumor suppressor signaling using therapeutic ephA2 agonists might offer new therapeutic opportunities to clinically widen the use of cetuximab in NRAS-mutated and/or ephA2-dependent mCRC tumors.
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July-2017
Volume 38 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Cuyàs E, Queralt B, Martin-Castillo B, Bosch-Barrera J and Menendez JA: EphA2 receptor activation with ephrin-A1 ligand restores cetuximab efficacy in NRAS-mutant colorectal cancer cells. Oncol Rep 38: 263-270, 2017.
APA
Cuyàs, E., Queralt, B., Martin-Castillo, B., Bosch-Barrera, J., & Menendez, J.A. (2017). EphA2 receptor activation with ephrin-A1 ligand restores cetuximab efficacy in NRAS-mutant colorectal cancer cells. Oncology Reports, 38, 263-270. https://doi.org/10.3892/or.2017.5682
MLA
Cuyàs, E., Queralt, B., Martin-Castillo, B., Bosch-Barrera, J., Menendez, J. A."EphA2 receptor activation with ephrin-A1 ligand restores cetuximab efficacy in NRAS-mutant colorectal cancer cells". Oncology Reports 38.1 (2017): 263-270.
Chicago
Cuyàs, E., Queralt, B., Martin-Castillo, B., Bosch-Barrera, J., Menendez, J. A."EphA2 receptor activation with ephrin-A1 ligand restores cetuximab efficacy in NRAS-mutant colorectal cancer cells". Oncology Reports 38, no. 1 (2017): 263-270. https://doi.org/10.3892/or.2017.5682