Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma

Abstract

Dedifferentiated liposarcoma (DDLPS) is an aggressive adipogenic cancer with poor prognosis. DDLPS tumors are only modestly sensitive to chemotherapy and radiation, and there is a need for more effective therapies. Genetically, DDLPS is characterized by a low tumor mutational burden and frequent chromosomal structural abnormalities including amplification of the 12q13-15 chromosomal region and the MDM2 gene, which are defining features of DDLPS. The MDM2 protein is an E3 ubiquitin ligase that targets the tumor suppressor, p53, for proteasomal degradation. MDM2 amplification or overexpression in human malignancies is associated with cell-cycle progression and worse prognosis. The MDM2-p53 interaction has thus garnered interest as a therapeutic target for DDLPS and other malignancies. MDM2 binds p53 via a hydrophobic protein interaction that is easily accessible with synthetic analogues. Multiple agents have been developed, including Nutlins such as RG7112 and small molecular inhibitors including SAR405838 and HDM201. Preclinical in vitro and animal models have shown promising results with MDM2 inhibition, resulting in robust p53 reactivation and cancer cell death. However, multiple early-phase clinical trials have failed to show a benefit with MDM2 pathway inhibition for DDLPS. Mechanisms of resistance are being elucidated, and novel inhibitors and combination therapies are currently under investigation. This review provides an overview of these strategies for targeting MDM2 in DDLPS.

Keywords: MDM2; clinical trial; dedifferentiated liposarcoma; p53; small molecular inhibitor; targeted therapy.

Figure 1

Clustered analysis of DNA copy number among soft-tissue sarcomas. Cluster C1 is primarily composed of leiomyosarcoma. Clusters C2 and C3 are primarily composed of dedifferentiated liposarcoma. Cluster C4 is composed of synovial sarcomas and malignant peripheral nerve sheath tumors. Cluster C5 is composed of high-grade undifferentiated pleomorphic sarcomas. Amplification in red, deletion in blue. Adapted from Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas (11).

Figure 2

Recurrent genetic alterations among 50 DDLPS samples. Amplification in red, deletions in blue. Green line indicates the significance threshold for focally amplified or deleted genes. Adapted from Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas (11).

Figure 3

Overview of the MDM2–p53 pathway in response to DNA damage. In the absence of DNA damage, MDM2 facilitates ubiquitination of p53, tagging it for proteosomal degradation. Damage to DNA activates kinases, including ataxia telangiectasia-mutated (ATM) kinase, which are responsible for phosphorylating MDM2 and reducing its affinity to bind cytosolic p53. Regulators of the MDM2–p53 interaction include the AKT/mTOR pathway, ARF, and c-MYC. Downstream transcriptional targets of p53 serve to arrest cell-cycle progression and induce cellular apoptosis. Multiple sites of action are targeted by MDM2 and MDM2–p53 inhibitors, which decrease p53 degradation in tumors with wild-type p53. Created with BioRender.com.