Oncotarget

Research Papers:

Time dependent modulation of tumor radiosensitivity by a pan HDAC inhibitor: abexinostat

Sofia Rivera, Céline Leteur, Frédérique Mégnin, Frédéric Law, Isabelle Martins, Ioana Kloos, Stéphane Depil, Nazanine Modjtahedi, Jean Luc Perfettini, Christophe Hennequin and Eric Deutsch _

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Oncotarget. 2017; 8:56210-56227. https://doi.org/10.18632/oncotarget.14813

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Abstract

Sofia Rivera1,2,3, Céline Leteur1,2, Frédérique Mégnin4, Frédéric Law1,2, Isabelle Martins1,2, Ioana Kloos5, Stéphane Depil5, Nazanine Modjtahedi1,2, Jean Luc Perfettini1,2, Christophe Hennequin6 and Eric Deutsch1,2,3

1Department of Radiotherapy, Gustave-Roussy Cancer Campus, Villejuif, France

2INSERM 1030 Molecular Radiotherapy, Villejuif, France

3Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France

4INSERM U1196/UMR9187 CMIB, Institut Curie-Recherche, Université Paris Saclay, Le Kremlin-Bicêtre, France

5IRIS: Institut de Recherches Internationales Servier, Suresnes, France

6Department of Radiation Oncology, Hôpital Saint Louis, APHP, Paris, France

Correspondence to:

Eric Deutsch, email: [email protected]

Keywords: epigenetics, radiosensitivity modulation, HDAC inhibitors, non-small cell lung cancer, radiotherapy

Received: July 22, 2016     Accepted: November 30, 2016     Published: January 25, 2017

ABSTRACT

Despite prominent role of radiotherapy in lung cancer management, there is an urgent need for strategies increasing therapeutic efficacy. Reversible epigenetic changes are promising targets for combination strategies using HDAC inhibitors (HDACi).

Here we evaluated on two NSCLC cell lines, the antitumor effect of abexinostat, a novel pan HDACi combined with irradiation in vitro in normoxia and hypoxia, by clonogenic assays, demonstrating that abexinostat enhances radiosensitivity in a time dependent way with mean SER10 between 1.6 and 2.5 for A549 and H460. We found, by immunofluorescence staining, flow cytometry assays and western blotting, in abexinostat treated cells, increasing radio-induced caspase dependent apoptosis and persistent DNA double-strand breaks associated with decreased DNA damage signalling and repair. Interestingly, we demonstrated on nude mice xenografts that abexinostat potentiates tumor growth delay in combined modality treatments associating not only abexinostat and irradiation but also when adding cisplatin.

Altogether, our data demonstrate in vitro and in vivo anti-tumor effect potentiation by abexinostat combined with irradiation in NSCLC. Moreover, our work suggests for the first time to our knowledge promising triple combination opportunities with HDACi, irradiation and cisplatin which deserves further investigations and could be of major interest in the treatment of NSCLC.


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