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OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations

Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models...

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Autores principales: Riveiro, Maria E., Astorgues-Xerri, Lucile, Vazquez, Ramiro, Frapolli, Roberta, Kwee, Ivo, Rinaldi, Andrea, Odore, Elodie, Rezai, Keyvan, Bekradda, Mohamed, Inghirami, Giorgio, D'Incalci, Maurizio, Noel, Kay, Cvitkovic, Esteban, Raymond, Eric, Bertoni, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354535/
https://www.ncbi.nlm.nih.gov/pubmed/27835869
http://dx.doi.org/10.18632/oncotarget.13181
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author Riveiro, Maria E.
Astorgues-Xerri, Lucile
Vazquez, Ramiro
Frapolli, Roberta
Kwee, Ivo
Rinaldi, Andrea
Odore, Elodie
Rezai, Keyvan
Bekradda, Mohamed
Inghirami, Giorgio
D'Incalci, Maurizio
Noel, Kay
Cvitkovic, Esteban
Raymond, Eric
Bertoni, Francesco
author_facet Riveiro, Maria E.
Astorgues-Xerri, Lucile
Vazquez, Ramiro
Frapolli, Roberta
Kwee, Ivo
Rinaldi, Andrea
Odore, Elodie
Rezai, Keyvan
Bekradda, Mohamed
Inghirami, Giorgio
D'Incalci, Maurizio
Noel, Kay
Cvitkovic, Esteban
Raymond, Eric
Bertoni, Francesco
author_sort Riveiro, Maria E.
collection PubMed
description Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo. Conversely, in SCLC models, weak antitumor activity was observed with OTX015, both in vitro and in vivo. No predictive biomarkers of OTX015 activity were identified in a large panel of candidate genes known to be affected by BET inhibition. In NSCLC models, OTX015 was equally active in both EML4-ALK positive and negative cell lines, whereas in SCLC models the presence of functional RB1 protein, which controls cell progression at G1, may be related to the final biological outcome of OTX015. Gene expression profiling in NSCLC and SCLC cell lines showed that OTX015 affects important genes and pathways with a very high overlapping between both sensitive and resistant cell lines. These data support the rationale for the OTX015 Phase Ib (NCT02259114) in solid tumors, where NSCLC patients with rearranged ALK gene or KRAS-positive mutations are currently being treated.
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spelling pubmed-53545352017-04-26 OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations Riveiro, Maria E. Astorgues-Xerri, Lucile Vazquez, Ramiro Frapolli, Roberta Kwee, Ivo Rinaldi, Andrea Odore, Elodie Rezai, Keyvan Bekradda, Mohamed Inghirami, Giorgio D'Incalci, Maurizio Noel, Kay Cvitkovic, Esteban Raymond, Eric Bertoni, Francesco Oncotarget Research Paper Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo. Conversely, in SCLC models, weak antitumor activity was observed with OTX015, both in vitro and in vivo. No predictive biomarkers of OTX015 activity were identified in a large panel of candidate genes known to be affected by BET inhibition. In NSCLC models, OTX015 was equally active in both EML4-ALK positive and negative cell lines, whereas in SCLC models the presence of functional RB1 protein, which controls cell progression at G1, may be related to the final biological outcome of OTX015. Gene expression profiling in NSCLC and SCLC cell lines showed that OTX015 affects important genes and pathways with a very high overlapping between both sensitive and resistant cell lines. These data support the rationale for the OTX015 Phase Ib (NCT02259114) in solid tumors, where NSCLC patients with rearranged ALK gene or KRAS-positive mutations are currently being treated. Impact Journals LLC 2016-11-07 /pmc/articles/PMC5354535/ /pubmed/27835869 http://dx.doi.org/10.18632/oncotarget.13181 Text en Copyright: © 2016 Riveiro et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Riveiro, Maria E.
Astorgues-Xerri, Lucile
Vazquez, Ramiro
Frapolli, Roberta
Kwee, Ivo
Rinaldi, Andrea
Odore, Elodie
Rezai, Keyvan
Bekradda, Mohamed
Inghirami, Giorgio
D'Incalci, Maurizio
Noel, Kay
Cvitkovic, Esteban
Raymond, Eric
Bertoni, Francesco
OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations
title OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations
title_full OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations
title_fullStr OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations
title_full_unstemmed OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations
title_short OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations
title_sort otx015 (mk-8628), a novel bet inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354535/
https://www.ncbi.nlm.nih.gov/pubmed/27835869
http://dx.doi.org/10.18632/oncotarget.13181
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