Beyond targeting amplified MDM2 and CDK4 in well differentiated and dedifferentiated liposarcomas: From promise and clinical applications towards identification of progression drivers

Abstract

Well differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS) are tumors of the adipose tissue poorly responsive to conventional cytotoxic chemotherapy which currently remains the standard-of-care. The dismal prognosis of the DDLPS subtype indicates an urgent need to identify new therapeutic targets to improve the patient outcome. The amplification of the two driver genes MDM2 and CDK4, shared by WDLPD and DDLPS, has provided the rationale to explore targeting the encoded ubiquitin-protein ligase and cell cycle regulating kinase as a therapeutic approach. Investigation of the genomic landscape of WD/DDLPS and preclinical studies have revealed additional potential targets such as receptor tyrosine kinases, the cell cycle kinase Aurora A, and the nuclear exporter XPO1. While the therapeutic significance of these targets is being investigated in clinical trials, insights into the molecular characteristics associated with dedifferentiation and progression from WDLPS to DDLPS highlighted additional genetic alterations including fusion transcripts generated by chromosomal rearrangements potentially providing new druggable targets (e.g. NTRK, MAP2K6). Recent years have witnessed the increasing use of patient-derived cell and tumor xenograft models which offer valuable tools to accelerate drug repurposing and combination studies. Implementation of integrated “multi-omics” investigations applied to models recapitulating WD/DDLPS genetics, histologic differentiation and biology, will hopefully lead to a better understanding of molecular alterations driving liposarcomagenesis and DDLPS progression, as well as to the identification of new therapies tailored on tumor histology and molecular profile.

Whole exome sequencing of well-differentiated liposarcoma and dedifferentiated liposarcoma in older woman: a case report

“…As sequencing technology has advanced, the molecular anomalies of WDLPS and DDLPS have been increasingly uncovered. Both WDLPS and DDLPS have high levels of chromosome 12q13-15 amplification ( 46 ), including CDK4, CPM, HMGA2, CPM, SAS/TSPAN31, YEATS4 ( 47 , 48 ), and overexpression of MDM2 as the key driver gene of 12q amplification, which is the initiating factor of WDLPS/DDLS carcinogenesis ( 49 ). The profiles of gene amplification in the 12q13-15 area differed significantly between WDLPS and DDLPS, with DDLPS exhibiting more significant levels of amplification than WDLPS.…”

New targeted therapies in liposarcoma: state of art and future perspectives

“…Possibly, information on the determinants of progression of WDLPS to DDLPS as well as factors influencing differentiation into different lineages (e.g., rhabdomyoblastic differentiation) may shed light on the identification of new therapeutic targets. DDLPS develop several secondary alterations during their development, and these may act as source of further therapeutic targets to be combined with inhibition of MDM2 or CDK4, as well as with conventional chemotherapy [33][34][35].…”

Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens

“…In 2006, investigators made the initial effort to combine MDM2 inhibitors and chemotherapy in order to stabilize wild-type p53, activate p53 activity, decrease proliferation, and enhance the vulnerability of cells to chemotherapy-induced apoptosis. In a preclinical study, it was observed that the combination of MDM2 inhibition with doxorubicin resulted in a considerable decrease in tumor growth compared to doxorubicin alone ( Bill et al, 2019 , Cassinelli et al, 2022 ). A previous investigation has revealed that neuroblastoma tumors often retain functional downstream p53 signaling pathways and exhibit wild-type p53 expression.…”