RG7112, a small-molecule inhibitor of MDM2, enhances trabectedin response in soft tissue sarcomas.
MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Selected sarcoma subtypes are being treated with Trabectedin in second line, which promotes DNA damage and p53-dependent apoptosis. The aim of this study was to evaluate the improvement of Trabectedin response with MDM2 inhibitors in soft tissue sarcomas. The antitumor effects of Trabectedin, Nutlin-3A and RG7112 as single agents or in combination were examined in vitro. RG7112 significantly synergized with Trabectedin in MDM2-amplified liposarcoma cells, representing a promising new therapeutic strategy for the treatment of sarcomas with MDM2 amplification.
a 1 Group of Advanced Therapies and Biomarkers in Clinical Oncology , Institut d'Investigació Sanitària de Palma (IdISPa) , Palma de Mallorca, Spain.|b 2 Department of Oncology , Hospital Universitari Son Espases, Palma de Mallorca , Spain.
Antònia
A
Obrador-Hevia
a 1 Group of Advanced Therapies and Biomarkers in Clinical Oncology , Institut d'Investigació Sanitària de Palma (IdISPa) , Palma de Mallorca, Spain.
Esther
E
Martinez-Font
c 3 Group of Molecular Oncology and New Therapies, Oncohematology and Genetics Department , Instituto de Biomedicina de Sevilla (IBiS) , Sevilla, Spain.
Irene
I
Felipe-Abrio
d 4 Molecular Oncology Laboratory, Fundación de Investigación , Hospital General Universitario de Valencia , Valencia, Spain.
Silvia
S
Calabuig-Fariñas
e 5 Cancer Cell Biology Group, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS) , University of the Balearic Islands , Palma de Mallorca, Spain.
Margalida
M
Serra-Sitjar
f 6 Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología , Valencia, Spain.
José Antonio
JA
López-Guerrero
g 7 Department of Pathology , Hospital Universitari Son Espases , Palma de Mallorca, Spain.
Rafael
R
Ramos
a 1 Group of Advanced Therapies and Biomarkers in Clinical Oncology , Institut d'Investigació Sanitària de Palma (IdISPa) , Palma de Mallorca, Spain.|h 8 Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS) , University of the Balearic Islands , Palma de Mallorca, Spain.
Regina
R
Alemany
c 3 Group of Molecular Oncology and New Therapies, Oncohematology and Genetics Department , Instituto de Biomedicina de Sevilla (IBiS) , Sevilla, Spain.|i 9 Department of Oncology , Hospital Universitario Virgen del Rocío , Sevilla, Spain.
Javier
J
Martín-Broto
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048288:Imidazolines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D004149:Dioxoles; D007093:Imidazoles; D048288:Imidazolines; D010879:Piperazines; C579783:RG7112; D044005:Tetrahydroisoquinolines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D000077606:Trabectedin
Liposarcoma; MDM2; RG7112; Soft tissue sarcomas; Trabectedin