RRC ID 62298
Author Okada Y, Kimura T, Nakagawa T, Okamoto K, Fukuya A, Goji T, Fujimoto S, Sogabe M, Miyamoto H, Muguruma N, Tsuji Y, Okahisa T, Takayama T.
Title EGFR Downregulation after Anti-EGFR Therapy Predicts the Antitumor Effect in Colorectal Cancer.
Journal Mol Cancer Res
Abstract Anti-EGFR mAb is reported to induce EGFR internalization in colorectal cancer cells. However, the biological relevance of EGFR internalization with anti-EGFR mAb is unknown. Therefore, the relevance of EGFR downregulation with anti-EGFR mAb to antitumor activity in colorectal cancer cells was investigated. Quantification of EGFR on the cell surface before cetuximab treatment was assessed by flow cytometry, and its growth-inhibitory effects were measured by Trypan blue exclusion, in 10 RAS, BRAF wild-type colorectal cancer cell lines, but there was no significant correlation between EGFR number and its growth-inhibitory effect. However, a significant correlation existed between the percentage decrease in the number of EGFRs after cetuximab treatment and its growth-inhibitory effect in those cell lines. Treatment with TGFα, a ligand for EGFR, induced EGFR internalization in colorectal cancer cells, but most EGFRs subsequently recycled to the cell surface, consistent with previous studies. While cetuximab treatment induced EGFR internalization, most receptors subsequently translocated into the late endosome, leading to lysosomal degradation, as revealed by immunoblotting and double immunofluorescence. Cetuximab-sensitive colorectal cancer cells showed greater EGFR internalization, stronger cell growth inhibition, and more augmented apoptotic signals than nonsensitive cells. IHC for EGFR, performed using an EGFR pharmDx Kit (mouse anti-human EGFR mAb clone 2-18C9), in clinical specimens before and after anti-EGFR mAb therapy in 13 colorectal cancer patients showed a significant correlation between the response to anti-EGFR mAb and decreased staining after therapy.Implications: This report clearly demonstrates that anti-EGFR mAb facilitates internalization and subsequent degradation of EGFRs in lysosomes, which is an important determinant of the efficacy of anti-EGFR mAb treatment for colorectal cancer. Mol Cancer Res; 15(10); 1445-54. ©2017 AACR.
Volume 15(10)
Pages 1445-1454
Published 2017-10-1
DOI 10.1158/1541-7786.MCR-16-0383
PII 1541-7786.MCR-16-0383
PMID 28698359
MeSH Adult Aged Antineoplastic Agents, Immunological / administration & dosage* Antineoplastic Agents, Immunological / pharmacology Caco-2 Cells Cell Line, Tumor Cell Survival / drug effects Cetuximab / administration & dosage* Cetuximab / pharmacology Colorectal Neoplasms / drug therapy* Colorectal Neoplasms / genetics Colorectal Neoplasms / metabolism Down-Regulation Endosomes / metabolism ErbB Receptors / genetics ErbB Receptors / metabolism* Female HCT116 Cells HT29 Cells Humans Male Middle Aged Proto-Oncogene Proteins B-raf / genetics Proto-Oncogene Proteins B-raf / metabolism Transforming Growth Factor alpha / pharmacology ras Proteins / genetics ras Proteins / metabolism
IF 4.63
Human and Animal Cells COLO205(RCB2127) JHCOLOYI(RCB1706) PMF-ko14(RCB1426)