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.
Highlights
Sarcoma accounts for approximately 1% of all cancers
This study indicates that fibroblast growth factor receptor (FGFR) inhibitors have therapeutic potential in the treatment of dedifferentiated liposarcoma (DDLPS) with amplified FRS2
In this study we investigated the case of a patient with high-grade metastatic retroperitoneal DDLPS with previously confirmed amplification of MDM2 and CDK4
Summary
Rare cancers together make up one of the largest patient groups and are by far the largest group with regards to lost years of life. This is largely due to the many heterogeneous subgroups, making research difficult and the interest from industry low. The present work is a demonstration of the potential of tumor sequencing to identify new therapeutic targets in sarcoma patients. Tumors in the extremities are in most cases successfully removed by surgery, whereas recurrence and progression is common for retroperitoneal tumors. Chemotherapy is usually ineffective, and progressive or metastatic retroperitoneal tumors are in www.impactjournals.com/oncotarget most cases fatal.
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