LINE-1 Expression is Associated with the Effectiveness of EGFR Inhibitors in Colorectal Cancer Cells

Abstract

Background: Colorectal cancer (CRC) sidedness is predictive of anti-epidermal growth factor receptor (anti-EGFR) antibody therapy effectiveness; however, the mechanism linking them is unclear. Long interspersed nuclear element-1 (LINE-1) methylation has been associated with sidedness. Here, we evaluated whether LINE-1 expression in CRC cell lines influenced the efficacy of EGFR inhibitors.Methods: We analyzed LINE-1 methylation in 98 clinical CRC samples. We also treated RAS-wild type SW48 and Caco-2 and RAS-mutant SW480, HCT116, and DLD-1 CRC cell lines with EGFR inhibitors gefitinib or RG14620, and performed growth assays in LINE-1-suppressed Caco-2, SW480, and DLD-1 cells.Results: Clinical CRC findings confirmed the association between LINE-1 methylation and sidedness. LINE-1 mRNA expression was high in SW480 and Caco-2 cells and low in HCT116 and SW48 cells. The half maximal inhibitory concentrations (IC50) of gefitinib were lower for LINE-1-expressing Caco-2 cells than for non-LINE-1-expressing SW48 cells, revealing an association between LINE-1 expression and the efficacy of gefitinib in RAS-wild type cells. LINE-1 knockdown increased the IC50 of gefitinib in Caco-2 cells. There was trend of increase in RG14620 IC50 upon LINE-1 knockdown even in RAS-mutant SW480 and DLD-1 cells, suggesting other mechanisms of RG14620 than EGFR signal inhibition.Conclusion: EGFR inhibitor gefitinib requires LINE-1 expression, and interventions targeting LINE-1 may increase its efficacy.

Keywords

• line-1
• egfr inhibitor
• colorectal cancer