Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma
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Robert Hanes1,2, Iwona Grad1, Susanne Lorenz1,2, Eva W. Stratford1, Else Munthe1, Chilamakuri Chandra Sekhar Reddy1,2, Leonardo A. Meza-Zepeda1,2,3,*, Ola Myklebost1,2,*
1Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
2Norwegian Cancer Genomics Consortium, Oslo, Norway
3Genomics Core Facility, Department of Core Facilities, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
*These authors have contributed equally and share last authorship
Ola Myklebost, email: [email protected]
Keywords: FRS2, NVP-BGJ398, liposarcoma, personalized genomics, targeted therapy
Received: November 23, 2015 Accepted: May 25, 2016 Published: July 09, 2016
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.
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