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

Maria E. Riveiro, Lucile Astorgues-Xerri, Ramiro Vazquez, Roberta Frapolli, Ivo Kwee, Andrea Rinaldi, Elodie Odore, Keyvan Rezai, Mohamed Bekradda, Giorgio Inghirami, Maurizio D'Incalci, Kay Noel, Esteban Cvitkovic, Eric Raymond, Francesco Bertoni

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)84675-84687
Number of pages13
JournalOncotarget
Volume7
Issue number51
DOIs
Publication statusPublished - 2016

Fingerprint

Small Cell Lung Carcinoma
Mutation
Cell Line
Down-Regulation
Genes
OTX015
Neoplasms
Gene Expression Profiling
Cell Cycle Checkpoints
Oncogenes
Epigenomics
Non-Small Cell Lung Carcinoma
Proteins
Biomarkers
Cell Proliferation
Messenger RNA

Keywords

  • Bromodomain
  • KRAS
  • NSCLC
  • OTX015 (MK-8628)
  • SCLC

ASJC Scopus subject areas

  • Oncology

Cite this

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.

In: Oncotarget, Vol. 7, No. 51, 2016, p. 84675-84687.

Research output: Contribution to journalArticle

Riveiro, ME, 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 2016, 'OTX015 (MK-8628), a novel BET inhibitor, exhibits antitumor activity in non-small cell and small cell lung cancer models harboring different oncogenic mutations', Oncotarget, vol. 7, no. 51, pp. 84675-84687. https://doi.org/10.18632/oncotarget.13181
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. In: Oncotarget. 2016 ; Vol. 7, No. 51. pp. 84675-84687.
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AU - Astorgues-Xerri, Lucile

AU - Vazquez, Ramiro

AU - Frapolli, Roberta

AU - Kwee, Ivo

AU - Rinaldi, Andrea

AU - Odore, Elodie

AU - Rezai, Keyvan

AU - Bekradda, Mohamed

AU - Inghirami, Giorgio

AU - D'Incalci, Maurizio

AU - Noel, Kay

AU - Cvitkovic, Esteban

AU - Raymond, Eric

AU - Bertoni, Francesco

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