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

Robert Hanes,Jianhua Han,Eva Stratford,Ola Myklebost,Else Munthe,Emmet Mccormack,Ida Karlsen,Iwona Grad,Leonardo Meza-Zepeda

doi:10.3390/cells8020189

Abstract

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

Highlights

Sarcomas are rare cancers of mesenchymal origin, accounting for approximately 1% of all solid cancers, and can be classified into more than 50 distinct histological subtypes [1].Liposarcomas (LPS), which resemble adipose tissue, are further classified into three main subtypes, well-differentiated/dedifferentiated liposarcoma (WD/DDLPS), myxoid/round cell liposarcoma, Cells 2019, 8, 189; doi:10.3390/cells8020189 www.mdpi.com/journal/cellsCells 2019, 8, 189 and pleomorphic liposarcoma [2]
NRH-LS1 cells exposed to 100 nM of LY2874455 were completely growth inhibited after 72 h (Figure 1A), while treatment with 100 nM NVP-BGJ398 gave only partial growth inhibition at that time point
FGF receptor inhibitors have shown tolerable toxicities in rodent and patients [10,11], showing efficacy in preclinical models could pave the way to clinical trials on sarcoma patients

Summary

Introduction

Sarcomas are rare cancers of mesenchymal origin, accounting for approximately 1% of all solid cancers, and can be classified into more than 50 distinct histological subtypes [1].Liposarcomas (LPS), which resemble adipose tissue, are further classified into three main subtypes, well-differentiated/dedifferentiated liposarcoma (WD/DDLPS), myxoid/round cell liposarcoma, Cells 2019, 8, 189; doi:10.3390/cells8020189 www.mdpi.com/journal/cellsCells 2019, 8, 189 and pleomorphic liposarcoma [2]. All together rare cancers comprise one of the largest patient groups, which is in great need of new therapeutic approaches. A deeper mechanistic understanding is needed to be able to identify and validate new potential targets. We identified amplifications of multiple genes in the 12q14.1-q15 region in the DDLPS cell line NRH-LS1 and investigated several of these as therapeutic targets [3]. FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified FRS2, but we previously only demonstrated transient cytostatic effects when treating FRS2-amplified DDLPS cells with NVP-BGJ398. Methods: Effects of the more potent FGFR inhibitor LY2874455 were investigated in three DDLPS cell lines by measuring effects on cell growth and apoptosis in vitro and testing efficacy in vivo. Transcriptome and protein analyses were performed to characterize the signaling components in the FGFR pathway

Methods

Results

Conclusion