Promising in vivo efficacy of the BET bromodomain inhibitor OTX015/MK-8628 in malignant pleural mesothelioma xenografts.
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.
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Ramiro
R
Vázquez
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Simonetta Andrea
SA
Licandro
Oncology Therapeutic Development, Clichy, France.
Lucile
L
Astorgues-Xerri
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Emanuele
E
Lettera
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Nicolò
N
Panini
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Michela
M
Romano
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Eugenio
E
Erba
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Paolo
P
Ubezio
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Ezia
E
Bello
Cytogenetic and Molecular Pathology Laboratory, Pathology Unit, Oncology, SS Antonio e Biagio e Cesare Arrigo General Hospital, Alessandria, Italy.
Roberta
R
Libener
Cytogenetic and Molecular Pathology Laboratory, Pathology Unit, Oncology, SS Antonio e Biagio e Cesare Arrigo General Hospital, Alessandria, Italy.
Sara
S
Orecchia
Cytogenetic and Molecular Pathology Laboratory, Pathology Unit, Oncology, SS Antonio e Biagio e Cesare Arrigo General Hospital, Alessandria, Italy.
Federica
F
Grosso
Oncology Therapeutic Development, Clichy, France.
María Eugenia
ME
Riveiro
Oncology Therapeutic Development, Clichy, France.|Oncoethix SA (now Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp), Lucerne, Switzerland.
Esteban
E
Cvitkovic
Oncology Therapeutic Development, Clichy, France.
Mohamed
M
Bekradda
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Maurizio
M
D'Incalci
Laboratory of Cancer Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Roberta
R
Frapolli
D000083:Acetanilides / Q000008:administration & dosage* / Q000494:pharmacology; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D051379:Mice; D008875:Middle Aged; D000068437:Pemetrexed / Q000008:administration & dosage* / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000083:Acetanilides; D006575:Heterocyclic Compounds, 3-Ring; C489427:MYC protein, human; C000605331:OTX015; D016271:Proto-Oncogene Proteins c-myc; D000068437:Pemetrexed; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine
MYC downregulation; OTX015/MK-8628; bromodomain inhibitor; mesothelioma