title: The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors.
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.
authors.affiliation: Raymond and Beverly Sackler Foundation Laboratory, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wong
authors.affiliation: 1] Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA [2] Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA [3] Center for Systems Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Laddha
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: L
authors.initials: L
authors.lastname: Tang
authors.affiliation: 1] Raymond and Beverly Sackler Foundation Laboratory, 195 Little Albany Street, New Brunswick, NJ 08901, USA [2] Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA [3] Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: E
authors.initials: E
authors.lastname: Vosburgh
authors.affiliation: 1] Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA [2] Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA [3] School of Natural Sciences, Institute for Advanced Study, 1 Einstein Drive, Princeton, NJ 08540, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Constellation Pharmaceuticals, Cambridge, MA 02142, USA.
authors.forename: E
authors.initials: E
authors.lastname: Normant
authors.affiliation: Constellation Pharmaceuticals, Cambridge, MA 02142, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sandy
authors.affiliation: 1] Raymond and Beverly Sackler Foundation Laboratory, 195 Little Albany Street, New Brunswick, NJ 08901, USA [2] Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA [3] Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Harris
authors.affiliation: 1] Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA [2] Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA [3] Center for Systems Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Chan
authors.affiliation: 1] Raymond and Beverly Sackler Foundation Laboratory, 195 Little Albany Street, New Brunswick, NJ 08901, USA [2] Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA [3] Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
authors.forename: E Y
authors.initials: EY
authors.lastname: Xu
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D020123:Sirolimus; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C000599185:CPI203