Background <p>Dedifferentiated liposarcoma (DDLPS) is characterized by amplification of cyclin-dependent kinase 4 (CDK4). However, responses to CDK4/6 inhibition have been heterogeneous. We sought to determine whether transcriptional heterogeneity in cell-cycle regulators define biologically distinct subtypes of DDLPS that contribute to CDK4/6 inhibitor sensitivity.</p> Methods <p>RNA sequencing data from The Cancer Genome Atlas sarcoma cohort (TCGA-SARC) were analyzed to identify DDLPS tumors (<i>N</i> = 57). Expression of key cell-cycle regulators was evaluated according to CDK4 expression to assess differences in cell-cycle regulation. Unsupervised clustering of cell-cycle regulators was performed to identify transcriptional subgroups and pathway activity across clusters was assessed.</p> Results <p>Initial comparison of tumors with high versus low CDK4 expression demonstrated differential expression of cell-cycle regulators, including increased CDK2 and CDKN2A expression in CDK4-high tumors. Unsupervised clustering identified three transcriptionally distinct subgroups characterized by patterns of CDK4 and CDK2 expression. These clusters were associated with divergent pathway activity profiles. One subgroup demonstrated high CDK4 expression with relatively low CDK2 activation and enrichment of inflammatory signaling pathways, suggesting continued reliance on the CDK4-RB axis. A second subgroup demonstrated concurrent activation of CDK4 and CDK2 alongside a proliferative transcriptional program, consistent with potential CDK2-mediated bypass of CDK4 signaling. A third subgroup demonstrated relatively low expression of both CDK4 and CDK2 with enrichment of hormone-associated signaling pathways.</p> Conclusions <p>DDLPS tumors exhibit distinct transcriptional states within the CDK4-RB regulatory network that may influence tumor dependence on CDK4 signaling. This may impact sensitivity to CDK4/6 inhibition and explain heterogeneous outcomes.</p>