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22.12.2016 | Research Article | Ausgabe 6/2017

Clinical and Translational Oncology 6/2017

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

Zeitschrift:
Clinical and Translational Oncology > Ausgabe 6/2017
Autoren:
S. S. Kumar, Y. Tomita, J. Wrin, M. Bruhn, A. Swalling, M. Mohammed, T. J. Price, J. E. Hardingham
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s12094-016-1596-8) contains supplementary material, which is available to authorized users.

Abstract

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.

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Zusatzmaterial
Supplementary material 1 (DOCX 268 kb)
12094_2016_1596_MOESM1_ESM.docx
Literatur
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