Abstract
Endogenous c-MYC (MYC) has been reported to be a potential pharmacological target to trigger ubiquitous tumor regression of pancreatic neuroendocrine tumors (PanNETs) and lung tumors. Recently inhibitors of bromodomain and extra-terminal (BET) family proteins have shown antitumor effects through the suppression of MYC in leukemia and lymphoma. In this paper, we investigated the antitumor activity of a BET protein bromodomain inhibitor (BETi) CPI203 as a single agent and in combination with rapamycin in human PanNETs. We found that exposure of human PanNET cell lines to CPI203 led to downregulation of MYC expression, G1 cell cycle arrest and nearly complete inhibition of cell proliferation. In addition, overexpression of MYC suppressed the growth inhibition caused by CPI203 and knockdown of MYC phenocopied the effects of CPI203 treatment. These findings indicate that suppression of MYC contributed to the antiproliferative effects of BETi inhibition in human PanNET cells. Importantly, CPI203 treatment enhanced the antitumor effects of rapamycin in PanNET cells grown in monolayer and in three-dimensional cell cultures, as well as in a human PanNET xenograft model in vivo. Furthermore, the combination treatment attenuated rapamycin-induced AKT activation, a major limitation of rapamycin therapy. Collectively, our data suggest that targeting MYC with a BETi may increase the therapeutic benefits of rapalogs in human PanNET patients. This provides a novel clinical strategy for PanNETs, and possibly for other tumors as well.
Highlights
C-MYC (MYC) is a potent oncogene that is frequently deregulated in a variety of cancers
Human pancreatic neuroendocrine tumors (PanNETs) cell lines are sensitive to BET protein bromodomain inhibitor (BETi)
To confirm the role of BETi in neuroendocrine tumors (NETs) cell growth, NET cell lines were treated with two other bromodomain and extraterminal (BET) inhibitors (+)-JQ1 and PFI-1 that displayed strong potency and specificity toward the acetyl-binding cavity of BET protein bromodomains.[13,15]
Summary
C-MYC (MYC) is a potent oncogene that is frequently deregulated in a variety of cancers. The BET proteins share a common structure with two N-terminal bromodomains that exhibit high levels of sequence conservation as well as an extra-terminal (ET) domain and a more divergent C-terminal recruitment domain. They function at the interface between chromatin remodeling and transcriptional regulation through binding to acetylated lysines on chromatin.[9] Miyoshi et al.[10] first described a thienodiazepine analog that competitively. Combination treatment of CPI203 with rapamycin showed stronger antiproliferative effects and decreased AKT activation in human PanNETs. Taken together, treatment with BETi and rapamycin critically lowered MYC and phospho-AKT, implicating that co-treatment may increase the response rate of patients
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