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<b>Background:</b> FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified <i>FRS2</i>, but we previously only demonstrated transient cytostatic effects when treating <i>FRS2</i>-amplified DDLPS cells with NVP-BGJ398. <b>Methods:</b> Effects of the more potent FGFR inhibitor LY2874455 were investigated in three DDLPS cell lines by measuring effects on cell growth and apoptosis <i>in vitro</i> and also testing efficacy <i>in vivo</i>. Genome, transcriptome and protein analyses were performed to characterize the signaling components in the FGFR pathway. <b>Results:</b> 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 <i>FRS2</i> amplification alone is not sufficient to predict response. Importantly, efficacy of LY2874455 was confirmed <i>in vivo</i>, using an independent <i>FRS2</i>-amplified DDLPS xenograft model. Expression of <i>FRS2</i> 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. <b>Conclusion:</b> Our study supports LY2874455 as a better therapy than NVP-BGJ398 for <i>FRS2</i>-amplified liposarcoma, and a clinical trial is warranted.