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ABSTRACT
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.
ACKNOWLEDGMENTS
We thank Pharmamar for providing Trabectedin and Roche for providing Nutlin-3A and RG7112. We thank the surgeons in Hospital Universitari Son Espases, Diego Salinas and Oscar Tendero, for providing patient's samples. We thank Dr. Florence Pedeutour for providing the 93T449 cell line. We thank Clara Martorell and Jordi Ginés for pharmacologic support.
FUNDING
This study was partially supported by the Institute of Health Carlos III (Ministerio de Economía y Competitividad) and the EC (European Regional Development Fund [ERDF]; PI12/01748). Research was also supported by Pharamar.
DECLARATION OF INTEREST
The authors report no conflicts of interest.
SUPPLEMENTAL MATERIAL AVAILABLE ONLINE
Supplementary Figures 1–3