Laroche-Clary Audrey, Chaire Vanessa, Algeo Marie-Paule, Derieppe Marie-Alix, Loarer François L, Italiano Antoine
Université de Bordeaux, Bordeaux, France.
Institut National de la Santé et de la Recherche Medicale (INSERM) U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux cedex, France.
J Hematol Oncol. 2017 Jun 19;10(1):123. 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.
MDM2和CDK4在高分化/去分化脂肪肉瘤（WDLPS/DDLPS）中常发生共扩增。我们旨在确定在DDLPS临床前模型中，联合靶向MDM2/CDK4是否比单一药物具有更高的抗肿瘤活性。
将DDLPS细胞暴露于RG7388（MDM2拮抗剂）和帕博西尼（CDK4抑制剂），通过流式细胞术和蛋白质印迹法监测细胞凋亡以及信号传导/生存途径的扰动。使用异种移植小鼠模型评估肿瘤生长和生存情况。通过蛋白质印迹法、组织病理学和肿瘤体积评估治疗效果。
RG7388和帕博西尼联合使用比单独使用任何一种药物都具有更强的抗肿瘤作用，在用RG7388和/或帕博西尼处理72小时后，细胞活力存在显著差异。与单一药物相比，联合治疗显著增加了细胞凋亡。然后，我们在DDLPS异种移植模型中分析了RG7388和帕博西尼的体内抗肿瘤活性。联合治疗方案与单独使用单一药物相比降低了肿瘤生长速率，并显著提高了无进展生存期的中位数。
我们的结果为评估CDK4抑制剂作为MDM2拮抗剂增效剂在DDLPS中的治疗潜力提供了有力依据，并证明了在这种情况下进行临床试验的合理性。
