PMID- 28005260 OWN - NLM STAT- MEDLINE DCOM- 20180312 LR - 20181202 IS - 1699-3055 (Electronic) IS - 1699-048X (Linking) VI - 19 IP - 6 DP - 2017 Jun TI - 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. PG - 718-726 LID - 10.1007/s12094-016-1596-8 [doi] AB - 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. FAU - Kumar, S S AU - Kumar SS AD - Basil Hetzel Institute, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011, Australia. AD - School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia. FAU - Tomita, Y AU - Tomita Y AD - School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia. AD - Basil Hetzel Institute and Department of Medical Oncology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011, Australia. FAU - Wrin, J AU - Wrin J AD - Basil Hetzel Institute, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011, Australia. AD - School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia. FAU - Bruhn, M AU - Bruhn M AD - Basil Hetzel Institute, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011, Australia. FAU - Swalling, A AU - Swalling A AD - Department of Anatomical Pathology, SA Pathology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011, Australia. FAU - Mohammed, M AU - Mohammed M AD - Department of Anatomical Pathology, SA Pathology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011, Australia. FAU - Price, T J AU - Price TJ AD - School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia. AD - Department of Medical Oncology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011, Australia. FAU - Hardingham, J E AU - Hardingham JE AUID- ORCID: 0000-0001-8277-1199 AD - Basil Hetzel Institute, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011, Australia. Jennifer.hardingham@adelaide.edu.au. AD - School of Medicine, University of Adelaide, Adelaide, SA, 5005, Australia. Jennifer.hardingham@adelaide.edu.au. LA - eng PT - Journal Article DEP - 20161222 PL - Italy TA - Clin Transl Oncol JT - Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico JID - 101247119 RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (EGR1 protein, human) RN - 0 (Early Growth Response Protein 1) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - PQX0D8J21J (Cetuximab) SB - IM MH - Antineoplastic Agents/*therapeutic use MH - Biomarkers, Tumor/analysis MH - Cetuximab/*therapeutic use MH - Cohort Studies MH - Colorectal Neoplasms/*drug therapy/mortality MH - Drug Resistance, Neoplasm/*genetics MH - Early Growth Response Protein 1/*biosynthesis MH - ErbB Receptors/antagonists & inhibitors MH - Humans MH - Kaplan-Meier Estimate MH - Pilot Projects OTO - NOTNLM OT - Anti-EGFR therapy OT - Colorectal cancer OT - EGR1 OT - Predictive biomarker OT - Resistance EDAT- 2016/12/23 06:00 MHDA- 2018/03/13 06:00 CRDT- 2016/12/23 06:00 PHST- 2016/09/29 00:00 [received] PHST- 2016/12/10 00:00 [accepted] PHST- 2016/12/23 06:00 [pubmed] PHST- 2018/03/13 06:00 [medline] PHST- 2016/12/23 06:00 [entrez] AID - 10.1007/s12094-016-1596-8 [pii] AID - 10.1007/s12094-016-1596-8 [doi] PST - ppublish SO - Clin Transl Oncol. 2017 Jun;19(6):718-726. doi: 10.1007/s12094-016-1596-8. Epub 2016 Dec 22.