In the present study, we investigated the significance of PI3K/Akt/ERK in poorly differentiated chemo-resistant esophageal adenocarcinoma (PDEAC) and explored the molecular mechanism of antitumor effects of GPC-1 knockdown alone or in combination with Pictilisib using in vitro and preclinical in vivo tumorigenesis model. This evidence concerns the gene GPC1 and esophageal adenocarcinoma.