title: A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth.
abstract: Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin-mediated signaling. However, continued requirement of Wnt/β-catenin signaling for tumor progression in the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-molecule tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt/β-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approximately 50% inhibition of APC mutation-driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic.
authors.affiliation: Department of Cancer Targets, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Lau
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Marinella
authors.initials: M
authors.lastname: Callow
authors.forename: Jo
authors.initials: J
authors.lastname: Waaler
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
authors.forename: Robert A
authors.initials: RA
authors.lastname: Blake
authors.forename: Steven
authors.initials: S
authors.lastname: Magnuson
authors.forename: Amy
authors.initials: A
authors.lastname: Sambrone
authors.forename: Melissa
authors.initials: M
authors.lastname: Schutten
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.forename: Ondrej
authors.initials: O
authors.lastname: Machon
authors.forename: Vladimir
authors.initials: V
authors.lastname: Korinek
authors.forename: Edna
authors.initials: E
authors.lastname: Choo
authors.forename: Dolores
authors.initials: D
authors.lastname: Diaz
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Holsworth
authors.forename: Stefan
authors.initials: S
authors.lastname: Krauss
authors.forename: Mike
authors.initials: M
authors.lastname: Costa
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017491:Genes, APC; D006801:Humans; D051379:Mice; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000502:physiology
chemical_list: D060466:Axin Protein; D004791:Enzyme Inhibitors; D010880:Piperidines; D013450:Sulfones; D038501:Tankyrases; D014230:Triazoles; D051176:beta Catenin; C495270:CTNNB1 protein, human; C582305:G007-LK; C582304:G244-LM; C418109:TNKS protein, human