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

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State: Public
Version: Final published version
Serval ID
serval:BIB_39F9023C76CA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
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.
Journal
Oncotarget
Author(s)
Riveiro M.E., Astorgues-Xerri L., Vazquez R., Frapolli R., Kwee I., Rinaldi A., Odore E., Rezai K., Bekradda M., Inghirami G., D'Incalci M., Noel K., Cvitkovic E., Raymond E., Bertoni F.
ISSN
1949-2553 (Electronic)
ISSN-L
1949-2553
Publication state
Published
Issued date
20/12/2016
Peer-reviewed
Oui
Volume
7
Number
51
Pages
84675-84687
Language
english
Notes
Publication types: Comparative Study ; Journal Article
Publication Status: ppublish
Abstract
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.

Keywords
Acetanilides/pharmacology, Animals, Antineoplastic Agents/pharmacology, Carcinoma, Non-Small-Cell Lung/drug therapy, Carcinoma, Non-Small-Cell Lung/genetics, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Female, Gene Expression Regulation, Heterocyclic Compounds, 3-Ring/pharmacology, Humans, Lung Neoplasms/drug therapy, Lung Neoplasms/genetics, Mice, Mice, Nude, Mutation/genetics, Protein-Serine-Threonine Kinases/antagonists & inhibitors, Receptor Protein-Tyrosine Kinases/genetics, Small Cell Lung Carcinoma/drug therapy, Small Cell Lung Carcinoma/genetics, Xenograft Model Antitumor Assays, KRAS, NSCLC, OTX015 (MK-8628), SCLC, bromodomain
Pubmed
Web of science
Open Access
Yes
Create date
05/12/2016 18:40
Last modification date
20/08/2019 13:29
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