Cargando…
γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct
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 pharm...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494507/ https://www.ncbi.nlm.nih.gov/pubmed/28539479 http://dx.doi.org/10.15252/emmm.201607265 |
_version_ | 1783247687464779776 |
---|---|
author | Ran, Yong Hossain, Fokhrul Pannuti, Antonio Lessard, Christian B Ladd, Gabriela Z Jung, Joo In Minter, Lisa M Osborne, Barbara A Miele, Lucio Golde, Todd E |
author_facet | Ran, Yong Hossain, Fokhrul Pannuti, Antonio Lessard, Christian B Ladd, Gabriela Z Jung, Joo In Minter, Lisa M Osborne, Barbara A Miele, Lucio Golde, Todd E |
author_sort | Ran, Yong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5494507 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54945072017-07-05 γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct Ran, Yong Hossain, Fokhrul Pannuti, Antonio Lessard, Christian B Ladd, Gabriela Z Jung, Joo In Minter, Lisa M Osborne, Barbara A Miele, Lucio Golde, Todd E EMBO Mol Med Research Articles 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. John Wiley and Sons Inc. 2017-05-24 2017-07 /pmc/articles/PMC5494507/ /pubmed/28539479 http://dx.doi.org/10.15252/emmm.201607265 Text en © 2017 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Ran, Yong Hossain, Fokhrul Pannuti, Antonio Lessard, Christian B Ladd, Gabriela Z Jung, Joo In Minter, Lisa M Osborne, Barbara A Miele, Lucio Golde, Todd E γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct |
title | γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct |
title_full | γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct |
title_fullStr | γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct |
title_full_unstemmed | γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct |
title_short | γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct |
title_sort | γ‐secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494507/ https://www.ncbi.nlm.nih.gov/pubmed/28539479 http://dx.doi.org/10.15252/emmm.201607265 |
work_keys_str_mv | AT ranyong gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct AT hossainfokhrul gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct AT pannutiantonio gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct AT lessardchristianb gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct AT laddgabrielaz gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct AT jungjooin gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct AT minterlisam gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct AT osbornebarbaraa gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct AT mielelucio gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct AT goldetodde gsecretaseinhibitorsincancerclinicaltrialsarepharmacologicallyandfunctionallydistinct |