Epigenetic Targeting of Aberrant Transcriptional Modulation in Pancreatic Cancer

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.

Altered histone acetylation patterns in pancreatic cancer cell lines induce subtype‑specific transcriptomic and phenotypical changes

“…The cellular subtype, drug dosage of the HDACi, as well as targeted HDAC classes, are essential to assess the functional and therapeutic outcome for HDACi. Although several approaches have investigated HDACi as a therapy option for pancreatic cancer, either as mono-therapy or in combination with chemotherapeutic drugs or targeted therapies ( 14 , 41 ), more systematic studies are needed. Further investigations focusing on a prior selection of patients that would benefit from epigenetic therapy are essential to target epigenetic modifications.…”

Pancreatic Cancer Heterogeneity Can Be Explained Beyond the Genome

“…Inhibiting HDACs could result in the activation of tumor suppressor genes leading to an inhibition of tumor cell proliferation. Until now, pancreatic cancer research has mostly focused on acetylation marks by studying HDAC inhibitors and proteins containing the bromodomain and extraterminal domain (BET), which recognizes or “reads” acetylation marks (14). It has been shown that the BET inhibitor JQ1 (also known as TEN-010 or thienotriazolodiazepine) suppresses the tumor growth in patient-derived xenograft models (15).…”