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  3. γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct

γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct

  • EMBO Mol Med. 2017 Jul;9(7):950-966. doi: 10.15252/emmm.201607265.
Yong Ran 1,  Fokhrul Hossain 2,  Antonio Pannuti 2,  Christian B Lessard 3,  Gabriela Z Ladd 4,  Joo In Jung 3,  Lisa M Minter 5,  Barbara A Osborne 5,  Lucio Miele 2,  Todd E Golde 1
Affiliations

Affiliations

  • 1 Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA yran@ufl.edu tgolde@ufl.edu.
  • 2 Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
  • 3 Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, and McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
  • 4 College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • 5 Department of Veterinary and Animal Sciences and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA, USA.
PMID: 28539479 DOI: 10.15252/emmm.201607265
Abstract

γ-secretase inhibitors (GSIs) are being actively repurposed as Cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various Notch substrates, with some enhancing cleavage of other Notch substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase (SPP/SPPL) family members. Extending these findings to mammosphere inhibition assays in triple-negative breast Cancer lines, we establish that these GSIs have different functional effects. We also demonstrate that the processive γ-secretase cleavage pattern established for amyloid precursor protein (APP) occurs in multiple substrates and that potentiation of γ-secretase cleavage is attributable to a direct action of low concentrations of GSIs on γ-secretase. Such data definitively demonstrate that the clinical GSIs are not biological equivalents, and provide an important framework to evaluate results from ongoing and completed human trials with these compounds.

Keywords

NOTCH; cancer therapy; γ‐secretase inhibitors.

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