Abstract 26: Panitumumab interacts with TAS-102 leading to combinational anti-cancer effects by blocking EGFR-mediated tumor response to trifluridine

Panitumumabis a monoclonal antibody raised 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 (mCRC). In this study, we show the mechanism underlying the anti-cancer effects of the panitumumab/TAS-102 combination in preclinical models. Co-treatment with panitumumaband FTD exerted additive and synergistic anti-proliferative effects in LIM1215 and SW48 colon cancer cells, respectively. Consistent with the in vitro effects, panitumumab/TAS-102 combination led to tumor regression in LIM1215 and COL-01-JCK colon cancer patient-derived xenograft models. In LIM1215 cells, FTD induced ERK/Akt/STAT3 phosphorylation and subsequent serine/threonine phosphorylation 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 the FTD-induced ERK/Akt/STAT3 and EGFR serine/threonine phosphorylation. These results suggested that FTD together with the basal activity of the EGFR tyrosine kinase induced downstream pro-survival signaling through ERK/Akt/STAT3. Collectively, we propose that panitumumabinteracts with FTD by targeting EGFR-mediated adaptive responses, thereby exerting anti-cancer effects in combination with TAS-102. These preclinical findings provide a compelling rationale to evaluate anti-EGFR antibodies combined with TAS-102 against mCRC. Citation Format: Kazuhide Nakamura, Yuji Baba, Toshiya Tamura, Yoshihiko Satoh, Masamitsu Gotou, Hiroshi Sawada, Shunsuke Ebara, Kazunori Shibuya, Jumpei Soeda. Panitumumabinteracts with TAS-102 leading to combinational anti-cancer effects by blocking EGFR-mediated tumor response to trifluridine[abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 26. doi:10.1158/1538-7445.AM2017-26