Abstract
Although histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is associated with poor overall prognosis and resistance to both conventional and emerging therapies
We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes in cancer-associated fibroblast (CAF) and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions
HTERT immortalized pancreatic ductal adenocarcinoma (PDAC) CAFs were found to be highly sensitive to suberanilohydroxamic acid (SAHA), which is similar to MIA PaCa2 cancer cells with an IC50 of 4 μM (Figure 1C)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is associated with poor overall prognosis and resistance to both conventional and emerging therapies. Gemcitabine is the most frequently used chemotherapy for PDAC, but at best, it increases survival by just a few weeks in both early- and advanced-stage patients [1]. Over the last 10 years, there have only been three new drugs approved by the FDA for PDAC, each of which confers only modest survival improvement in advanced-stage patients. In 2005, erlotinib, an EGFR inhibitor, was approved after being shown to increase survival by an average of 10 days as compared to gemcitabine alone [2]. In 2014, a nanoparticle coated with albumin and packaged with paclitaxel (nab-paclitaxel) was approved after demonstrating 2 months additional survival over gemcitabine [3]. Liposomal irinotecan combined with fluorouracil/leucovorin has been approved for advanced-stage disease, adding a modest 2 months additional survival compared to fluorouracil alone. As PDAC is predicted to become the second leading cause of cancer-related deaths in the United States within the 10 years, there is an ever-pressing need to identify new therapies that are broadly effective against this difficult to treat malignancy [4]
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