Panitumumab interaction with TAS-102 leads to combinational anticancer effects via blocking of EGFR-mediated tumor response to trifluridine

Panitumumabis a monoclonal antibody developed against the human epidermal growth factor receptor (EGFR). TAS-102 is a novel chemotherapeutic agent containing trifluridine(FTD) as the active cytotoxic component. Both panitumumaband TAS-102 have been approved for the treatment of metastatic colorectal cancer. In this study, we revealed the mechanism underlying the anticancer effects of panitumumab/TAS-102 combination using preclinical models. Panitumumab/FTD co-treatment showed additive antiproliferative effects in LIM1215 and synergistic antiproliferative effects in SW48 colon cancer cells. Consistent with the in vitro effects, panitumumab/TAS-102 combination caused tumor regression in LIM1215 and COL-01-JCK colon cancer patient-derived xenograft models. In LIM1215 cells, FTD induced extracellular signal-regulated kinase (ERK)/ protein kinase B(AKT)/signal transducer and activator of transcription 3 ( STAT3) phosphorylation and subsequent serine/ threoninephosphorylation of EGFR, while it had no effects on EGFR tyrosine phosphorylation. Panitumumaband the tyrosine kinase inhibitor erlotinibreduced the basal level of EGFR tyrosine phosphorylationand reversed FTD-induced ERK/AKT/ STAT3and EGFR serine/ threoninephosphorylation. These results suggested that FTD in combination with the basal activity of EGFR tyrosine kinase induced downstream prosurvival signaling through ERK/AKT/ STAT3phosphorylation. Collectively, we propose that panitumumabinteracts with FTD by targeting EGFR-mediated adaptive responses, thereby exerting anticancer effects when used in combination with TAS-102. These preclinical findings provide a compelling rationale for evaluating the combination of anti-EGFR antibodies with TAS-102 against metastatic colorectal cancer.