title: The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer due in part to a lack of highly robust cytotoxic or molecular-based therapies. Recent studies investigating ligand-mediated Wnt/β-catenin signaling have highlighted its importance in pancreatic cancer initiation and progression, as well as its potential as a therapeutic target in PDAC. The small-molecule ICG-001 binds cAMP-responsive element binding (CREB)-binding protein (CBP) to disrupt its interaction with β-catenin and inhibit CBP function as a coactivator of Wnt/β-catenin-mediated transcription. Given its ability to inhibit Wnt/β-catenin-mediated transcription in vitro and in vivo, as well as its efficacy in preclinical models of colorectal cancer and other Wnt-driven diseases, we examined ICG-001 and its potential role as a therapeutic in PDAC. ICG-001 alone significantly inhibited anchorage-dependent and -independent growth of multiple PDAC lines, and augmented in vitro growth inhibition when used in combination with gemcitabine. ICG-001 had only variable modest effects on PDAC apoptosis and instead mediated PDAC growth inhibition primarily through robust induction of G₁ cell-cycle arrest. These effects, however, seemed decoupled from its inhibition of Wnt/β-catenin-mediated transcription. DNA microarrays performed on PDAC cells in the context of ICG-001 treatment revealed ICG-001 altered the expression of several genes with well-established roles in DNA replication and cell-cycle progression, including direct actions on SKP2 and CDKN1A. ICG-001 also significantly prolonged survival in an in vivo orthotopic xenograft model of PDAC, indicating ICG-001 or derived compounds that disrupt CBP activity are potentially useful small-molecule therapeutics for pancreatic cancer.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Arensman
authors.affiliation: Department of Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Donatello
authors.initials: D
authors.lastname: Telesca
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Lay
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Kershaw
authors.affiliation: Deparment of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Nanping
authors.initials: N
authors.lastname: Wu
authors.affiliation: Deparment of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Donahue
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California. ddawson@mednet.ucla.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011744:Pyrimidinones / Q000494:pharmacology*; D011897:Random Allocation; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D011744:Pyrimidinones; D050882:CREB-Binding Protein; C494363:CREBBP protein, human
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