Epidermal growth factor receptor mRNA expression: A potential molecular escape mechanism from regorafenib

Abstract

Regorafenib has improved the survival of patients with refractory metastatic colorectal cancer (mCRC), yet the mechanisms of inherited or acquired resistance are not well understood. A total of 50 patients with refractory mCRC were enrolled.Circulating tumor cell (CTC) enumeration was carried out at baseline, day 21 after initiation of regorafenib, and at the time of progression of disease (PD) using the CellSearch System (Veridex LLC, NJ, USA). Poly(A) mRNA was extracted from CTCs, and gene expression of epithelial and epithelial-mesenchymal transition markers was analyzed by a multiplex-PCR based DNA Chip. Patients with fewer than 3 CTCs at baseline and day 21 had a longer progression-free survival than those with 3 or more CTCs (3.3 vs 2.0 months, P = .008 and 3.3 vs 2.0 months, P = .004, respectively).Patients with fewer than 3 CTCs at baseline and day 21 had a longer overall survival (OS) than those with 3 or more CTCs (10.0 vs 4.6 months, P < .001 and 8.7 vs 3.8 months, P = .003, respectively). In multivariable analysis, CTC counts remained significantly associated with OS at baseline and day 21 (P = .019 and P = .028).Circulating tumor cell EGFR gene expression was upregulated at day 21 and/or PD in 64% of patients. Patients had significantly increased EGFR expression at PD compared to baseline (P = .041) and at day 21 and/or PD compared to baseline (P = .004).Our findings suggest that CTC count and EGFR expression could be useful markers of regorafenib efficacy and outcomes. Upregulation of CTC EGFR expression might be a molecular escape mechanism under regorafenib therapy. K E Y W O R D S circulating tumor cell, colorectal cancer, epidermal growth factor receptor, epithelial marker and EMT, regorafenib How to cite this article: Matsusaka S, Hanna DL, Ning Y, et al.Epidermal growth factor receptor mRNA expression: A potential molecular escape mechanism from regorafenib.

Detection and clinical significance of circulating tumor cells in colorectal cancer

“…Regorafenib is a vascular endothelial growth factor receptor (VEGFR) inhibitor, and Satoshi et al found that the expression of EGFR in CTCs was significantly increased in patients who received regorafenib and were evaluated for progression after treatment compared to baseline CTCs. The authors concluded that increased EGFR expression may be a pattern of resistance and provided supporting evidence for the synergistic effect of regorafenib and anti-EGFR drugs [ 118 ] (Fig. 3 e).…”

“…Patients had significantly increased EGFR expressionat day 21 and/or PD compared to baseline. [ 118 ] 94 MACS RT-qPCR EpCAM – – Patients with higher gene panel expression (composed of GAPDH, VIL1, CLU, TIMP1,TLN1, LOXL3 and ZEB2) at baseline or increased gene panel expression duringtreatment had decreased PFS and OS. This CTC detection panel had increasedreliability compared to computed tomography scan.…”

“…Reproduced with permission from reference [ 115 ]; e Copyright Wiley 2020. Reproduced with permission from reference [ 118 ] …”

Rationale for Early Detection of EWSR1 Translocation-Associated Sarcoma Biomarkers in Liquid Biopsy

“…The detection of a rare cell requires an extended series of sampling; in practical terms, this means processing millions of cells to distinguish a real population of CTC. This process is greatly enhanced by techniques such as flow cytometry, wherein cells can be analysed at the rate of thousands per second, or automated image analysis, but is still hampered by the rarity of events; one commercially available system ‘Veridex’ (CellSearch®) has been approved by the U.S. Food and Drug Administration [ 119 ]. The technical hurdle of extended measurement can be overcome by enriching the target population within the sample, by amplifying the signal or a combination of both.…”

Research and application of single-cell sequencing in tumor heterogeneity and drug resistance of circulating tumor cells

“…Therefore, increasing studies are conducted on tumor resistance through CTC. Scholars study choriocarcinoma [ 22 ], colorectal cancer [ 23 – 26 ], liver cancer [ 27 ], lung cancer [ 28 , 29 ], breast cancer [ 30 , 31 ], lymphoma [ 32 ], gastric cancer [ 33 ] and other malignant tumors through CTC to explore the drug resistance of tumor cells. However, most current CTC analyses are based on CTC epithelial biomarkers, and epithelial biomarkers may not be expressed in several tumor types [ 34 ].…”