P23. Transcriptional heterogeneity in dedifferentiated liposarcoma reveals distinct cell-cycle subtypes

Introduction: Our previous work in ER⁺/HER2⁻ breast cancer demonstrated that cell cycle plasticity underlies fractional resistance to CDK4/6 inhibition. Given the near universal CDK4 amplification in dedifferentiated liposarcoma (DDLPS) and heterogeneous responses to CDK4/6 inhibitors, variability in cell cycle regulation may impact sensitivity to CDK4/6 inhibitors. In this study we used gene expression data to define subtypes of dedifferentiated liposarcoma based on differential expression of cell cycle regulator genes to understand the landscape of cell cycle regulation that may contribute to variable CDK4/6i sensitivity.


Methods: RNA-sequencing data from The Cancer Genome Atlas (TCGA-SARC) were filtered for DDLPS cases (N=57). Expression values for key cell-cycle regulators (CDK4, CDK6, CCNA2, CCNB1, CCNE1, E2F1, RB1, MKI67, CDKN2A, CDK2) were z-score normalized and grouped using unsupervised spectral clustering. Cluster-level expression differences were analyzed and descriptive statistics were performed.


Results: Three transcriptionally distinct DDLPS subtypes were identified, reflecting differential activation of cell-cycle genes. The “Sensitive-like” subtype demonstrated lower expression of proliferation-associated genes and maintained features of RB-mediated control, consistent with canonical CDK4/6 dependence. In contrast, the “Resistant-like” subtype exhibited a hyperproliferative transcriptional profile with elevated E2F1, CCNE1, CCNA2, CCNB1, CDK2, and MKI67, suggesting functional bypass of the CDK4/6-RB checkpoint. A third, intermediate cluster showed partial overlap between the two phenotypes. Violin and heatmap analyses confirmed these differences, with clear segregation of proliferative markers between clusters (Figure 1A-B). Although CDK4 expression was uniformly high, variability in downstream regulators appeared to drive divergence in pathway activation, supporting intrinsic resistance in a subset of tumors.


Conclusions: Transcriptomic clustering of TCGA DDLPS reveals molecular subtypes defined by distinct activation cell cycle mediators. These findings mirror resistance mechanisms described in breast cancer, suggesting that cell cycle plasticity resulting in escape from CDK4/6 mediated cell cycle arrest may be conserved across tumor types. These findings inform future studies to determine biomarkers to select patients for CDK4/6i therapy.