Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cancer in the United States. Till date PDAC has shockingly poor outcome, as it can not be detected at an early stage and has a very aggressive phenotype that is resistant to standard therapies. Previous reports from our lab have depicted that the effect of most commonly used drug to treat PDAC, Gemcitabine, has limited effect and develops resistance due to the presence of a ECM oncoprotein, CYR61/CCN1. Depletion of CYR61/CCN1 protein suppresses invasive phenotypes and remarkably improves the treatment outcome of Gemcitabine in PDAC in-vitro and in-vivo. Hence, a potent synthetic chemical inhibitor of CYR61/CCN1 is essential to make it druggable.

Objective: Zoledronic acid (ZOL) is a FDA approved medication used to treat many bone diseases including osteoporosis, high blood calcium and bone breakdown due to cancer and Paget’s disease of bone. Moreover, earlier studies have shown that ZOL significantly blocks pancreatic cancer cell migration and invasion. Thus, in this proposed study, we investigated whether ZOL blocks CYR61/CCN1 expression in PDAC cells to inhibit invasive phenotypes.

Results: Pancreatic cell lines (Panc-1 and AsPC-1) were treated with various concentrations of ZOL for different times points. Cells have shown no signs of stress physically as well as in molecular level. CYR61/CCN1 expression decreased significantly in a time and dose dependent manner at both transcriptional and translational level in PDAC cells and mouse (G12D/+; p53R172H/+; PdxCretg/+ -KPC) primary tumor-derived organoids. We compared the phenotypic alteration resulting due to CYR61/CCN1 downregulation and they reflect reduced stemness, low cell migration and cell proliferation. We treated the cells with exogenous human recombinant CYR61/CCN1 protein along with ZOL treatment and the cells regained/rescued their parental phenotype significantly. This led us to identify the CYR61/CCN1 as a target of ZOL in PDAC cells. Additionally, we found that ZOL treatment or CYR61/CCN1 depletion significantly reduces the expression of PD-L1 (encoded by the CD274 gene), which plays a role in suppressing immune system in many cancers including PDAC. As ZOL can reduce the levels of CYR61/CCN1 and PD-L1, that could act as an added advantage to use this drug in PDAC via suppressing CYR61/CCN1. Additionally, ZOL with targeted-nano-carriers were equally effective in regulation of CYR61/CCN1.

Conclusion: Our results suggest that ZOL could be repurposed as a CYR61/CCN1 inhibitor in PDAC in-vitro and in-vivo. Additionally, ZOL has the ability to block PD-L1 activity that could prove beneficial towards pancreatic cancer treatment. Furthermore, our studies suggest that CYR61/CCN1 is druggable for PDAC and beyond.

Citation Format: Arnab Ghosh, Sandipto Sarkar, Sonia Ghosh, Priyanka Ray, Mohi Quadir, Sushanta K. Banerjee, Snigdha Banerjee. Zoledronic acid-induced suppression of invasive phenotypes of pancreatic cancer cells is mediated through downregulation of CYR61/CCN1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1234.