Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma

Abstract

Sarcomas are rare cancers with limited treatment options. Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery, and would benefit from new personalized approaches. In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines. We have analyzed three metastases from a patient with high-grade metastatic dedifferentiated liposarcoma (DDLPS) by exome and transcriptome sequencing as well as DNA copy number analysis. Genomic aberrations of several potentially targetable genes, including amplification of KITLG and FRS2, in addition to amplification of CDK4 and MDM2, characteristic of this disease, were identified. We evaluated the efficacy of drugs targeting these aberrations or the corresponding signaling pathways in a cell line derived from the patient. Interestingly, the pan-FGFR inhibitor NVP-BGJ398, which targets FGFR upstream of FRS2, strongly inhibited cell proliferation in vitro and induced an accumulation of cells into the G0 phase of the cell cycle. This study indicates that FGFR inhibitors have therapeutic potential in the treatment of DDLPS with amplified FRS2.

Amplification of FRS2 in atypical lipomatous tumour/well‐differentiated liposarcoma and de‐differentiated liposarcoma: a clinicopathological and genetic study of 146 cases

“…validated the FRS2 amplification in DDLs (14 of 15, 93%) and found that the FGFR/FRS2 pathway was activated in 75% of high‐grade liposarcomas . Most recently, another study detected FRS2 amplification in the metastatic tumours of a DDL patient …”

“…24 Most recently, another study detected FRS2 amplification in the metastatic tumours of a DDL patient. 25 To evaluate more clearly the frequency of FRS2 amplification in ALT/WDL/DDL and understand the tumorigenic mechanism underlying this entity further, we analysed a large series of ALT/WDL/DDL at one of the largest medical centres in China. To our knowledge, this is the largest cohort in the English language literature.…”

Protein Tyrosine Phosphatase Receptor Type G (PTPRG) Controls Fibroblast Growth Factor Receptor (FGFR) 1 Activity and Influences Sensitivity to FGFR Kinase Inhibitors

“…Supernatants were incubated with 300 μl StreptavidinSepharose High Performance for 2 hours. Beads were collected and washed twice for 5 minutes at 4°C in 1% Triton X-100, 500 mM NaCl, 1 mM EDTA, twice for 5 min at 4°C in PBS with 0.1% Triton X-100, twice for 5 minutes at room temperature in 2% SDS, twice for 9 5 minutes at room temperature in 6 M Urea in PBS, and six times for 5 minutes at room temperature in 1 M NaCl, 25% Acetonitrile and twice for 5 min at room temperature in 20%…”

“…There have also been reported effects of FGFR inhibitors in osteosarcoma cells without apparent FGFR aberrations, indicating that other mechanisms for FGFR vulnerability exist (9,13). To increase the impact of FGFR inhibitors, it is crucial to understand in detail how their action on FGFR signaling and cell viability is determined.…”

The phosphatase PTPRG controls FGFR1 activity and influences sensitivity to FGFR kinase inhibitors

“…osteosarcoma, rhabdomyosarcoma (RMS) and soft tissue sarcoma) (Weekes et al, 2016, Guagnano et al, 2012, Taylor et al, 2009, Chudasama et al, 2016, Zhou et al, 2016). In addition, the FGFR-specific downstream signalling adaptor, the FGFR substrate 2 (FRS2), is overexpressed in liposarcoma and render these cells sensitive to FGFR inhibitors (Hanes et al, 2016, Zhang et al, 2013).…”