Research Papers:

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 and Francesco Bertoni

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Oncotarget. 2016; 7:84675-84687. https://doi.org/10.18632/oncotarget.13181

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Maria E. Riveiro1, Lucile Astorgues-Xerri1, Ramiro Vazquez2, Roberta Frapolli2, Ivo Kwee3,5, Andrea Rinaldi3, Elodie Odore6, Keyvan Rezai6, Mohamed Bekradda1, Giorgio Inghirami7,9, Maurizio D’Incalci2, Kay Noel10, Esteban Cvitkovic1,10, Eric Raymond11, Francesco Bertoni3,12

1Oncology Therapeutic Development, Clichy, France

2IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

3Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland

4Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland

5SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland

6Radiopharmacology Department, Curie Institute - René Huguenin Hospital, Saint Cloud, France

7Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

8Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Turin, Italy

9Department of Pathology, and NYU Cancer Center, New York University School of Medicine, New York, NY, USA

10Oncoethix SA (now Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp and Dohme Corp.), Lucerne, Switzerland

11Medical Oncology Department, CHUV, Lausanne, Switzerland

12Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland

Correspondence to:

Maria E Riveiro, email: [email protected]

Keywords: OTX015 (MK-8628), bromodomain, NSCLC, SCLC, KRAS

Received: January 21, 2016     Accepted: October 14, 2016     Published: November 07, 2016


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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