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. 2017 Dec 1;7(12):2587-2599.
eCollection 2017.

Arginine methylation of EGFR: a new biomarker for predicting resistance to anti-EGFR treatment

Krittiya Korphaisarn  1   2 , Chao-Kai Chou  3 , Wei-Ya Xia  3 , Callisia N Clarke  2 , Riham Katkhuda  4 , Jennifer S Davis  5 , Kanwal Ps Raghav  2 , Hsin-Wei Liao  6 , Ji-Yuan Wu  2 , David G Menter  2 , Dipen M Maru  4 , Mien-Chie Hung  3   7   8 , Scott Kopetz  2
Affiliations

Arginine methylation of EGFR: a new biomarker for predicting resistance to anti-EGFR treatment

Krittiya Korphaisarn et al. Am J Cancer Res. .

Abstract

Arginine methylation of the epidermal growth factor receptor (meEGFR) increases the binding affinity of EGFR ligands and is reported to have a role in predicting response to anti-EGFR agents. This study investigated the predictive impact of meEGFR in metastatic colorectal cancer (mCRC) patients treated with anti-EGFR agents. Two patient cohorts were evaluated. Cohort 1 consisted of mCRC patients with documented disease progression following anti-EGFR treatment. Circulating tumor cells (CTCs) were isolated and distinguished based on CD45- and Epcam+. Cohort 2 consisted of formalin fixed paraffin-embedded (FFPE) blocks from a prospective cohort. meEGFR in both cohorts was identified by positive staining for me-R198/200 EGFR signal. CTCs were identified in 30 out of 47 cases in cohort 1. Of those 30, meEGFR-CTCs were identified in 19 cases. Mean total meEGFR-CTCs counts was 2.3 (range 0-30) cells per 7.5 ml. There was no association between meEGFR-CTCs and clinic-pathological-molecular features. In RASwt/BRAFwt patients with high levels of meEGFR-CTCs ratio (≥ 0.23) had significantly inferior PFS with anti-EGFR treatment (HR = 3.4, 95% CI 1.5-7.9, P = 0.004). By contrast, high levels of meEGFR in the untreated tumor tissues had no correlation with anti-EGFR treatment duration in cohort 2. Therefore, meEGFR-CTCs may have the potential to serve as a "liquid biopsy" biomarker to predict anti-EGFR treatment efficacy.

Keywords: EGFR; Liquid biopsy; arginine methylation; circulating tumor cells; colorectal cancer; predictive marker.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Total CTCs and meEGFR-CTCs detected. CTCs were identified in 30 out of 47 cases (63.8%). Of these 30 cases, meEGFR-CTCs were identified in 19 cases (63.3%).
Figure 2
Figure 2
Ratio of meEGFR per total CTCs. The mean ratio of mEGFR CTCs to total CTCs was 0.23 with the range from 0 to 1.
Figure 3
Figure 3
Kaplan-Meier survival curve of RAS wt BRAF wt mCRC. A. RASwt BRAFwt mCRC patients with high meEGFR ratio (≥ 0.23) had significantly worse PFS for anti-EGFR treatment (median PFS 5.3 mo, 95% CI 3.5-7 mo) compared with pts with the ratio < 0.23 (median PFS 8 mo, 95% CI 1.7-14.2 mo, P = 0.002). B. There was no correlation between high or low meEGFR expression in the tumor tissues and PFS for anti-EGFR treatment treatment (median PFS 7.4 mo, 95% CI 5.0-9.7 mo in low expression compared with median PFS 9.5 mo, 95% CI 2.9-16.0 mo in high expression, P = 0.46).
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