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Published on: July 25, 2020
Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas
Audrey Laroche-Clary1,2, Vanessa Chaire1,2, Marie-Paule Algeo1
1Université de Bordeaux, Bordeaux, France.
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.
Insights
Combining MDM2 and CDK4 inhibitors shows greater anti-tumor activity in dedifferentiated liposarcoma (DDLPS) models. This dual targeting significantly increases apoptosis and reduces tumor growth compared to single agents.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) frequently exhibits co-amplification of MDM2 and CDK4 genes.
- Targeting these amplified oncogenes presents a potential therapeutic strategy for DDLPS.
Purpose of the Study:
- To investigate the combined anti-tumor activity of MDM2 and CDK4 inhibitors in preclinical DDLPS models.
- To compare the efficacy of combined targeting versus single-agent therapy.
Main Methods:
- DDLPS cell lines were treated with RG7388 (MDM2 antagonist) and palbociclib (CDK4 inhibitor).
- Apoptosis, signaling pathways, cell viability, and tumor growth in xenograft models were assessed.
- Western blotting, flow cytometry, and histopathology were utilized for analysis.
Main Results:
- Combined RG7388 and palbociclib demonstrated superior anti-tumor effects compared to individual drugs.
- Combination therapy significantly enhanced apoptosis and reduced cell viability in vitro.
- In vivo studies showed reduced tumor growth rate and increased progression-free survival with the combination regimen.
Conclusions:
- Combined targeting of MDM2 and CDK4 offers enhanced anti-tumor activity in DDLPS.
- CDK4 inhibitors may potentiate MDM2 antagonists in DDLPS treatment.
- These findings support the clinical evaluation of combination therapy for DDLPS.
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