title: Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model.
abstract: BACKGROUND
  Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014.
  
  
  METHODS
  A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting.
  
  
  RESULTS
  We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active β-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours.
  
  
  CONCLUSIONS
  This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.
authors.affiliation: Department of Medicine, University of Colorado Cancer Center, University of Colorado Denver, Aurora, CO, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Arcaroli
authors.forename: K S
authors.initials: KS
authors.lastname: Quackenbush
authors.forename: A
authors.initials: A
authors.lastname: Purkey
authors.forename: R W
authors.initials: RW
authors.lastname: Powell
authors.forename: T M
authors.initials: TM
authors.lastname: Pitts
authors.forename: S
authors.initials: S
authors.lastname: Bagby
authors.forename: A C
authors.initials: AC
authors.lastname: Tan
authors.forename: B
authors.initials: B
authors.lastname: Cross
authors.forename: K
authors.initials: K
authors.lastname: McPhillips
authors.forename: E-K
authors.initials: EK
authors.lastname: Song
authors.forename: W M
authors.initials: WM
authors.lastname: Tai
authors.forename: R A
authors.initials: RA
authors.lastname: Winn
authors.forename: K
authors.initials: K
authors.lastname: Bikkavilli
authors.forename: M
authors.initials: M
authors.lastname: Vanscoyk
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: W A
authors.initials: WA
authors.lastname: Messersmith
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D011897:Random Allocation; D051880:Receptors, Notch / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D051880:Receptors, Notch; D013764:Tetrahydronaphthalenes; D053829:Amyloid Precursor Protein Secretases; D014633:Valine; C550722:nirogacestat