Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas

Journal of Hematology & Oncology

François L. Loarer¹  Antoine Italiano²  Marie-Paule Algeo³  Marie-Alix Derieppe³  Vanessa Chaire³  Audrey Laroche-Clary³ 

[1] Department of Medical Oncology, Institut Bergonié;Institut National de la Santé et de la Recherche Medicale (INSERM) U1218, Institut Bergonié;Université de Bordeaux;

关键词: MDM2;    CDK4;    Well-differentiated/dedifferentiated liposarcomas;   

DOI  :  10.1186/s13045-017-0482-3

来源: DOAJ

【 摘 要 】

Abstract Purpose 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. Experimental design 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. Results 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. Conclusions 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.

【 授权许可】

Unknown