Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma.

FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified , but we previously only demonstrated transient cytostatic effects when treating -amplified DDLPS cells with NVP-BGJ398. Effects of the more potent FGFR inhibitor LY2874455 were investigated in three DDLPS cell lines by measuring effects on cell growth and apoptosis and also testing efficacy . Genome, transcriptome and protein analyses were performed to characterize the signaling components in the FGFR pathway. LY2874455 induced a stronger, longer-lasting growth inhibitory effect and moderate level of apoptosis for two cell lines. The third cell line, did not respond to FGFR inhibition, suggesting that amplification alone is not sufficient to predict response. Importantly, efficacy of LY2874455 was confirmed , using an independent -amplified DDLPS xenograft model. Expression of was similar in the responding and non-responding cell lines and we could not find any major difference in downstream FGFR signaling. The only FGF expressed by unstimulated non-responding cells was the intracellular ligand FGF11, whereas the responding cell lines expressed extracellular ligand FGF2. Our study supports LY2874455 as a better therapy than NVP-BGJ398 for -amplified liposarcoma, and a clinical trial is warranted.