High early growth response 1 (EGR1) expression correlates with resistance to anti-EGFR treatment in vitro and with poorer outcome in metastatic colorectal cancer patients treated with cetuximab

• S. S. Kumar ^[1] ; J. E. Hardingham ^[1] ; T. J. Price ^[2] ; M. Bruhn ^[1] ; Y. Tomita ^[2] ; J. Wrin ^[1] ; A. Swalling ^[1] ; M. Mohammed ^[1]
  1. [1] The Queen Elizabeth HospitalWoodvilleAustralia
  2. [2] University of AdelaideAdelaideAustralia
• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 19, Nº. 6, 2017, págs. 718-726
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • Purpose Biomarkers, such as mutant RAS, predict resistance to anti-EGFR therapy in only a proportion of patients, and hence, other predictive biomarkers are needed. The aims were to identify candidate genes upregulated in colorectal cancer cell lines resistant to anti-EGFR monoclonal antibody treatment, to knockdown (KD) these genes in the resistant cell lines to determine if sensitivity to anti-EGFR antibody was restored, and finally to perform a pilot correlative study of EGR1 expression and outcomes in a cohort of metastatic colorectal cancer (mCRC) patients given cetuximab therapy.

    Methods Comparative expression array analysis of resistant cell lines (SW48, COLO-320DM, and SNU-C1) vs sensitive cell lines (LIM1215, CaCo2, and SW948) was performed. The highest up-regulated gene in each resistant cell line was knocked down (KD) using RNA interference, and effect on proliferation was assessed with and without anti-EGFR treatment. Expression of the candidate genes in patients’ tumours treated with cetuximab was assessed by immunohistochemistry; survival analyses were performed comparing high vs low expression.

    Results Genes significantly upregulated in resistant cell lines were EGR1 (early growth response protein 1), HBEGF (heparin-binding epidermal growth factor-like growth factor), and AKT3 (AKT serine/threonine kinase 3). KD of each gene resulted in the respective cells being more sensitive to anti-EGFR treatment, suggesting that the resistant phenotype was reversed. In the pilot study of mCRC patients treated with cetuximab, both median PFS (1.38 months vs 6.79 months; HR 2.77 95% CI 1.2–19.4) and median OS (2.59 months vs 9.82 months; HR 3.0 95% CI 1.3–23.2) were significantly worse for those patients with high EGR1 expression.

    Conclusion High EGR1 expression may be a candidate biomarker of resistance to anti-EGFR therapy.