Abstract
While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances in cancer management and research. Consequently, there is an urgent need to find new and unconventional therapeutic targets to improve prognosis and survival of pancreatic cancer patients. In this review, we discuss the transcriptional effects of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal domain (BET) and Histone Deacetylase (HDAC) inhibitors, which are currently highly promising therapeutic options. We suggest that these inhibitors can be better utilized at lower doses which exploit their transcriptional modulatory effects on pancreatic cancer transcriptional programs directed by specific factors such as MYC and Forkhead Box A1 (FOXA1), rather than simply based on their anti-proliferative effects. This approach can potentially help avoid the intolerable adverse events frequently elicited by the use of these treatments at higher doses. In particular, we underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner.
Highlights
We focus on the transcriptional mechanisms of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal (BET) and Histone Deacetylase (HDAC) inhibitors, which represent promising therapeutic options
Epigenetic agents are a special subclass of drugs whose targets and effects are dependent on the epigenetic and transcriptional landscape of each system
We speculate that administering these agents at these doses likely influences their specificity and probably promotes many of the intolerable adverse effects that might lead to premature termination of clinical studies
Summary
While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7% [1,2]. Epigenetic pathways affect transcription either via modulation of histone modifications which can be activating or silencing, DNA methylation-mediated silencing, non-coding RNAs, and alteration of chromatin accessibility [9] This meshwork provides the cells with various tools that can dramatically affect its transcriptome without the need to induce any irreversible changes at the level of the genome. We focus on the transcriptional mechanisms of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal (BET) and Histone Deacetylase (HDAC) inhibitors, which represent promising therapeutic options We suggest that these inhibitors can be better utilized for their transcriptional modulation, rather than solely on their anti-proliferative effects, which can lead to intolerable adverse events. We underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner
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