Role of CDK4 as prognostic biomarker and synergistic effect of its inhibition in dedifferentiated liposarcoma sequential treatment

Abstract

Background Soft tissue sarcomas represent a heterogeneous group of rare mesenchymal tumors comprising 1% of all solid malignancies. Among them liposarcoma is one of the most common histotypes, with atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma (ALT/WDLPS and DDLPS) as the major sub entities. The unavailability of predictive, prognostic and druggable biomarkers make the management of these lesions challenging. In recent years, CDK4 and its inhibitors have emerged as potential weapons for these lesions especially for ALT/WDLPS and DDLPS but the results are not conclusive and need to be elucidated. Methods This study involved 21 ALT/WDLPS and DDLPS patients. Histological analyses of MDM2 and CDK4 were carried out. Moreover, a DDLPS patient-derived cancer model was established in vitro and in vivo assessing the efficacy of palbociclib in combination and sequential treatment. Finally, in silico analyses on CDK4 expression were carried out. Results The results showed a higher expression of CDK4 and MDM2 in DDLPS compared to ALT/WDLPS. Moreover, no correlation between MDM2 expression and CDK4 was observed. In addition, CDK4 expression seemed to correlate with specific anatomic regions. Next, in vitro analysis of CDK4 inhibitor palbociclib showed an antagonistic effect when combined to other chemotherapeutics, while it exhibited a significant synergy when administered in sequential schedule in both 2D and 3D culture models with ifosfamide, ifosfamide plus epirubicin, trabectedin, dacarbazine, eribulin and lenvatinib. The data were further corroborated by scratch wound healing assay and live-dead analysis. Next, in vivo analysis on DDLPS xenotransplanted embryos assessing the efficacy and safety profile of the in vitro tested schedules confirmed the observed data. Finally, in silico analysis supported the role of CDK4 in sarcoma management, especially DDLPS. Conclusion This proof-of-concept study sheds light on the natural history of ALT/WDLPS and DDLPS and provides the rationale for the clinical applicability of sequential treatment with palbociclib in the management of DDLPS.