Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas

• Published in: Journal of hematology and oncology Vol. 10; no. 1; p. 123
• Main Authors: Laroche-Clary, Audrey, Chaire, Vanessa, Algeo, Marie-Paule, Derieppe, Marie-Alix, Loarer, François L, Italiano, Antoine
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 19.06.2017; BioMed Central; BMC
• Subjects: Animal models; Animals; Antagonists; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Breast cancer; Cancer therapies; CDK4; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chromosomes; Clinical trials; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - metabolism; Development and progression; Drug Synergism; Drug therapy; Female; Flow cytometry; Gene amplification; Gene expression; Genetic aspects; Growth rate; Hematology; Humans; Liposarcoma; Liposarcoma - drug therapy; Liposarcoma - metabolism; Liposarcoma - pathology; MDM2; MDM2 protein; Mice; Molecular Targeted Therapy; Oncology; para-Aminobenzoates - pharmacology; para-Aminobenzoates - therapeutic use; Patients; Physiological aspects; Piperazines - pharmacology; Piperazines - therapeutic use; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; Pyridines - pharmacology; Pyridines - therapeutic use; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Rapid Communication; Signal transduction; Survival; Tumors; Well-differentiated/dedifferentiated liposarcomas; Western blotting; Xenografts; France; MDM2; CDK4; Well-differentiated/dedifferentiated liposarcomas
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-017-0482-3

MDM2 and CDK4 are frequently co-amplified in well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS. DDLPS cells were exposed to RG7388 (MDM2 antagonist) and palbociclib (CDK4 inhibitor), and apoptosis and signalling/survival pathway perturbations were monitored by flow cytometry and Western blotting. Xenograft mouse models were used to assess tumour growth and survival. Treatment efficacy was assessed by Western blotting, histopathology and tumour volume. RG7388 and palbociclib together exerted a greater antitumour effect than either drug alone, with significant differences in cell viability after a 72-h treatment with RG7388 and/or palbociclib. The combination treatment significantly increased apoptosis compared to the single agents. We then analysed the in vivo antitumour activity of RG7388 and palbociclib in a xenograft model of DDLPS. The combination regimen reduced the tumour growth rate compared with a single agent alone and significantly increased the median progression-free survival. Our results provide a strong rationale for evaluating the therapeutic potential of CDK4 inhibitors as potentiators of MDM2 antagonists in DDLPS and justify clinical trials in this setting.