Novel Therapeutic Insights in Dedifferentiated Liposarcoma: A Role for FGFR and MDM2 Dual Targeting

SIMPLE SUMMARY: Well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) are the most frequent soft tissue sarcomas. Despite the hopes raised by some targeted therapies, effective well-tolerated treatments for DDLPS are still lacking. Small-molecule FGFR inhibitors are currently evaluated in advanced clinical trials including the potent FDA-approved pan-FGFR inhibitor erdafitinib. We provide the first analysis of FGFR1-4 expression and their prognostic value in a series of 694 WDLPS/DDLPS samples. We identified FGFR1 and FGFR4 as prognostic biomarkers. We demonstrated erdafitinib efficacy and showed that erdafitinib combination with the MDM2 antagonist idasanutlin was highly synergistic in vitro and in vivo. The clinical relevance of our findings was supported by our data on a patient with DDLPS refractory to multiple lines of treatment whose tumor was stabilized for 12 weeks on erdafitinib. These data provide a rationale to use FGFR expression as a biomarker to select patients for clinical trials investigating FGFR inhibitors and to test combined erdafitinib and idasanutlin. ABSTRACT: We aimed to evaluate the therapeutic potential of the pan-FGFR inhibitor erdafitinib to treat dedifferentiated liposarcoma (DDLPS). FGFR expression and their prognostic value were assessed in a series of 694 samples of well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). The effect of erdafitinib—alone or in combination with other antagonists—on tumorigenicity was evaluated in vitro and in vivo. We detected overexpression of FGFR1 and/or FGFR4 in a subset of WDLPS and DDLPS and demonstrated correlation of this expression with poor prognosis. Erdafitinib treatment reduced cell viability, inducing apoptosis and strong inhibition of the ERK1/2 pathway. Combining erdafitinib with the MDM2 antagonist RG7388 exerted a synergistic effect on viability, apoptosis, and clonogenicity in one WDLPS and two DDLPS cell lines. Efficacy of this combination was confirmed in vivo on a DDLPS xenograft. Importantly, we report the efficacy of erdafitinib in one patient with refractory DDLPS showing disease stabilization for 12 weeks. We provide evidence that the FGFR pathway has therapeutic potential for a subset of DDLPS and that an FGFR1/FGFR4 expression might constitute a powerful biomarker to select patients for FGFR inhibitor clinical trials. In addition, we show that combining erdafitinib with RG7388 is a promising strategy for patients with DDLPS that deserves further investigation in the clinical setting.