MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies.

Stephanie Verbeke,Antoine Italiano,Audrey Laroche-Clary,Marie-Alix Derieppe,Shomereeta Roy

doi:10.3390/cancers12082253

Stephanie Verbeke, Antoine Italiano + Show 3 more

Open Access

https://doi.org/10.3390/cancers12082253

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Journal: Cancers	Publication Date: Aug 12, 2020
Citations: 10	License type: CC BY 4.0

Affiliation: Institut Bergonié, Inserm, University of Bordeaux

Abstract

The MDM2 gene is amplified in dedifferentiated liposarcoma (DDLPS). Treatment with MDM2 antagonists is a promising strategy to treat DDLPS; however, drug resistance is a major limitation when these drugs are used as a single agent. This study examined the impact of MDM2 antagonists on the mitogen-activated protein kinase (MAPK) pathway in DDLPS and investigated the potential synergistic activity of a MAPK kinase (MEK) inhibitor in combination with MDM2 antagonists. We identified a synergistic effect and identified the mechanism behind it. Combination effects of MDM2 antagonists and a MEK inhibitor were analyzed in a patient-derived xenograft mouse model and in DDLPS and leiomyosarcoma cell lines using different cell proliferation assays and immunoblot analysis. MDM2 antagonist (RG7388)-resistant IB115 [P4] cells and p53-silenced DDLPS cells were also established to understand the importance of functional p53. We found that MDM2 antagonists induced an upregulation of phosphorylated extracellular signal-regulated kinase (p-ERK) in DDLPS cells. The upregulation of p-ERK occurred due to mitochondrial translocation of p53, which resulted in increased production of reactive oxygen species, causing the activation of receptor tyrosine kinases (RTKs). Activated RTKs led to the activation of the downstream MEK/ERK signaling pathway. Treatment with a MEK inhibitor resulted in decreased expression of p-ERK, causing significant anti-tumor synergy when combined with MDM2 antagonists. Our results provide a framework for designing clinical studies of combination therapies in DDLPS patients.

Highlights

Dedifferentiated liposarcoma (DDLPS) is one of the most common subtypes of sarcoma
We observed that exposure of IB115 and IB111 cells to RG7388 or HDM201 induced a significant increase in the expression of phosphorylated extracellular signal-regulated kinase (p-ERK), along with increase in the expression of p53 (Figure 1B–E)
We did not observe any change in the expression of p-ERK in the p53-null IB136 and IB112 cells treated with RG7388 or HDM201 (Figure 1F–I)

Summary

Introduction

Dedifferentiated liposarcoma (DDLPS) is one of the most common subtypes of sarcoma. Surgical resection in reference centers is the cornerstone of DDLPS treatment [1]. Locoregional recurrence occurs in more than 50% of cases, in tumors located in the retroperitoneum. Anthracycline-based chemotherapy is the standard first-line treatment in the advanced setting and is associated with very modest efficacy: the median progression-free survival for advanced DDLPS is less than 5 months [3]. MDM2 gene (12q13-15) amplification is the genetic hallmark of DDLPS [1,4,5]. This gene encodes an E3 ubiquitin ligase that ubiquitinates and causes the degradation of the tumor suppressor protein

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