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Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK‐8628 in malignant pleural mesothelioma xenografts
Author(s) -
Vázquez Ramiro,
Licandro Simonetta Andrea,
AstorguesXerri Lucile,
Lettera Emanuele,
Panini Nicolò,
Romano Michela,
Erba Eugenio,
Ubezio Paolo,
Bello Ezia,
Libener Roberta,
Orecchia Sara,
Grosso Federica,
Riveiro María Eugenia,
Cvitkovic Esteban,
Bekradda Mohamed,
D'Incalci Maurizio,
Frapolli Roberta
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30412
Subject(s) - pemetrexed , gemcitabine , mesothelioma , cancer research , bromodomain , cisplatin , in vivo , oncogene , cancer , cell culture , downregulation and upregulation , medicine , cell cycle , biology , chemotherapy , pathology , epigenetics , gene , biochemistry , microbiology and biotechnology , genetics
It has recently been reported that a large proportion of human malignant pleural mesothelioma (MPM) cell lines and patient tissue samples present high expression of the c‐MYC oncogene. This gene drives several tumorigenic processes and is overexpressed in many cancers. Although c‐MYC is a strategic target to restrain cancer processes, no drugs acting as c‐MYC inhibitors are available. The novel thienotriazolodiazepine small‐molecule bromodomain inhibitor OTX015/MK‐8628 has shown potent antiproliferative activity accompanied by c‐MYC downregulation in several tumor types. This study was designed to evaluate the growth inhibitory effect of OTX015 on patient‐derived MPM473, MPM487 and MPM60 mesothelioma cell lines and its antitumor activity in three patient‐derived xenograft models, MPM473, MPM487 and MPM484, comparing it with cisplatin, gemcitabine and pemetrexed, three agents which are currently used to treat MPM in the clinic. OTX015 caused a significant delay in cell growth both in vitro and in vivo . It was the most effective drug in MPM473 xenografts and showed a similar level of activity as the most efficient treatment in the other two MPM models (gemcitabine in MPM487 and cisplatin in MPM484). In vitro studies showed that OTX015 downregulated c‐MYC protein levels in both MPM473 and MPM487 cell lines. Our findings represent the first evidence of promising therapeutic activity of OTX015 in mesothelioma.