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Panitumumab is 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 panitumumab and 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 cotreatment 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/threonine phosphorylation of EGFR, while it had no effects on EGFR tyrosine phosphorylation. Panitumumab and the tyrosine kinase inhibitor erlotinib reduced the basal level of EGFR tyrosine phosphorylation and reversed FTD-induced ERK/AKT/STAT3 and EGFR serine/threonine phosphorylation. These results suggested that FTD in combination with the basal activity of EGFR tyrosine kinase induced downstream prosurvival signaling through ERK/AKT/STAT3 phosphorylation. Collectively, we propose that panitumumab interacts 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., (© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

The primary site of metastasis of bone and soft tissue sarcoma is the lung. Control of these sarcomas depends upon the prevention and treatment of their pulmonary metastasis. The introduction of a chemotherapy consisting mainly of Adriamycin and high-dose methotrexate dramatically improved the prognosis of osteosarcoma. However the effectiveness of chemotherapy has not yet been duplicated in soft tissue sarcomas except some childhood sarcomas. We analyzed the clinical data for pulmonary metastasis of osteosarcomas and soft tissue sarcomas. Based on these analyses, we tried to clarify the nature of pulmonary metastasis of these sarcomas and to evaluate its response to treatment, that this would yield clues to future treatment of these sarcomas.