Abstract 1837: MUC1 confers sensitivity to STAT-3 inhibitor napabucasin in pancreatic ductal adenocarcinoma cells
Authors: Bose Mukulika , Vora Aabha , Colleton Taylor , Mukherjee Pinku 
Published: September 2020

Introduction: Pancreatic cancer is the third leading cause of cancer-related deaths in the US and 95% of pancreatic cancers are Pancreatic Ductal Adenocarcinomas (PDACs). Napabucasin is a small molecule inhibitor that targets the signal transducer and activator of transcription 3 (STAT-3) pathway in cancer stem cells. Napabucasin in combination with nab-paclitaxel and gemcitabine, was under phase III clinical trials for gastroenterological cancers including Pancreatic Cancer. The trials have been stopped recently due to futility. Therefore, it is important to find subpopulations of tumor cells that are likely to respond better to Napabucasin treatment alone or as a combination. Mucin1 or MUC1 is a transmembrane glycoprotein found in almost all glandular epithelial cells, and is overexpressed and aberrantly glycosylated in greater than 80% of PDACs. The tumor form of MUC1 is associated with poor prognosis. In PDAC cells, MUC1 expression is critical for tumor cell survival, oncogenic signaling, metastasis, and conferring stemness. Phosphorylated STAT-3 is known to regulate MUC1 expression. Thus, we hypothesize that 1) the STAT-3-MUC1 survival pathway is constitutively activated in MUC1-high PDAC cells and 2) Napabucasin will be more effective in MUC1-high compared to MUC1-low PDAC cells. Methods: Human PDAC cell lines with varying levels of MUC1 (CFPAC, Capan 2, Capan 1, HPAF II, HS766T, BxPc3.MUC1 and BxPC3.Neo) and a normal pancreatic ductal epithelial cell line (HPDE) were treated with increasing doses of Napabucasin (0.05 uM, 0.1uM, 0.2uM, 0.4uM, 0.8uM, 1.6uM, 3.2uM, 6.4uM, 12.8uM and 25.6uM) for 48 and 72 hours. Following treatment, MTT and colony formation assays were performed to determine survival and growth respectively. Results: The cells with high MUC1, CFPAC and Capan 1 showed increased susceptibility to Napabucasin at lower doses (IC50 - 2.088uM and 0.371uM respectively) compared to cells with low MUC1, Capan 2 and HS766T (IC50 - 6.885uM and 7.464uM respectively). MUC1-high HPAF II cells were resistant even at high doses. Data further confirmed that the IC50 of Napabucasin was significantly lower for Bx.Pc3.MUC1 (1.86uM) compared to Bx.Pc3.Neo cells (23.19uM). MUC1-high expressing cell lines lost their colony forming potential at lower doses compared to MUC1-low expressing cell lines. To test if oncogenic signaling linked to MUC1 dimerization confers sensitivity to Napabucasin, the PDA cells were pre-treated with GO-203, a small molecule that inhibits dimerization of MUC1 which renders signaling through the MUC1 cytoplasmic tail non-functional. Conclusion: MUC1 induces susceptibility to Napabucasin in PDACs. Napabucasin has shown anti-tumor activity in preclinical models and early clinical trials of gastroenterological cancers. However, lack of specificity led to increased toxicities and decreased efficacy. It is important to identify and validate biomarkers that better identify patients who have upregulated stemness pathways. MUC1 is one such specific biomarker that could be incorporated in future clinical trials to help identify patient subpopulations that may most likely benefit from combination therapies with stemness-inhibiting drugs. Further study of the crosstalk between stemness signaling pathways is necessary to understand mechanisms of synergistic effects and treatment resistance.

Citation Format: Mukulika Bose, Aabha Vora, Taylor Colleton, Pinku Mukherjee. MUC1 confers sensitivity to STAT-3 inhibitor napabucasin in pancreatic ductal adenocarcinoma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1837.