TY - JOUR
T1 - Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts
AU - Vázquez, Ramiro
AU - Licandro, Simonetta Andrea
AU - Astorgues-Xerri, Lucile
AU - Lettera, Emanuele
AU - Panini, Nicolò
AU - Romano, Michela
AU - Erba, Eugenio
AU - Ubezio, Paolo
AU - Bello, Ezia
AU - Libener, Roberta
AU - Orecchia, Sara
AU - Grosso, Federica
AU - Riveiro, María Eugenia
AU - Cvitkovic, Esteban
AU - Bekradda, Mohamed
AU - D'Incalci, Maurizio
AU - Frapolli, Roberta
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - bromodomain inhibitor
KW - mesothelioma
KW - MYC downregulation
KW - OTX015/MK-8628
UR - http://www.scopus.com/inward/record.url?scp=84994477658&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994477658&partnerID=8YFLogxK
U2 - 10.1002/ijc.30412
DO - 10.1002/ijc.30412
M3 - Article
AN - SCOPUS:84994477658
VL - 140
SP - 197
EP - 207
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 1
ER -