Abstract 4673: A novel way to sensitize pancreatic cancer cells for gemcitabine treatment

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a dismal median survival of 6 months. While combining albumin-bound paclitaxel with gemcitabine has shown clear therapeutic advantage, numerous attempts using novel targeted therapies did not yield clinical benefits. Gemcitabine is still the first-line treatment for patients with PDAC. We hypothesize that strategies to increase gemcitabine sensitivity may be effective in PDAC treatment. In this study, we report that cancer stem cell regulator Sox2 is highly induced in acquired gemcitabine resistant pancreatic cell lines, and down-regulation of Sox2 sensitizes cancer cells to gemcitabine treatment both in the cultured cells and in mouse models. Down-regulation of Gli1/2 was associated with reduced Sox2 expression, decreased expression of cancer stem cell markers. We found Gli1/2 proteins in association with a Sox2 promoter sequence with a putative Gli binding site, suggesting a direct regulation of Sox2 by Gli1/2. We further showed that down-regulation of Gli1 or Gli2 was as effective as Sox2 knockdown in sensitizing cancer cells to gemcitabine treatment. The relevance of Gli1/2-Sox2 signaling axis to PDAC was suggested by association of high Sox2 expression with poor survival in stage II PDAC patients. Taken together, our data indicate an important role of non-canonical hedgehog signaling in regulation of gemcitabine sensitivity, and down-regulation of Gli1/2 transcription factors, together with gemcitabine, may be effective in pancreatic cancer treatment. Citation Format: Jingwu Xie, Dongsheng Gu, Xiaoli Zhang, Yanfei Jia, Gabi Chiorean. A novel way to sensitize pancreatic cancer cells for gemcitabine treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4673.