Src signaling is involved in chemoresistance and migration of chondrosarcoma cells Jolieke G. van Oosterwijk¹, Inge H. Briaire- de Bruijn¹, Maayke A.J.H. van Ruler¹, Bram Herpers², Hans Gelderblom³, Bob van de Water², Judith V.M.G. Bovée¹ ¹Dept of pathology, LUMC, Leiden, the Netherlands ²Dept of toxicology, LACDR, Leiden, the Netherlands ³Dept of clinical oncology, LUMC, Leiden, the Netherlands

2 No efficacious treatment for irresectable or metastatic chondrosarcoma exists Activation of AKT and Src pathways in Chondrosarcoma Identification of role of survival pathways in chemoresistance Background

3 Pepchip Schrage et al. Cancer Research 2009 AKT and Src activity in chondrosarcoma Pepchip IntensityMoleculesDescription AKT1V-AKT murine thymoma viral homolog GSK3βGlycogen synthase kinase 3β TTNTitin RPS6KA5Ribosomal protein S6 kinase alpha FYNFYN oncogene related SRC, FGR, YES LCKLymphocyte specific tyrosine kinase

4 PI3K/AKT is not involved in chemoresistance

5 Dasatinib overcomes chemoresistance

Dasatinib with doxorubicin induces apoptosis

7 Fyn is the most important Src family member N=137: 92 central CS, 45 peripheral CS

8 Dasatinib inhibits cell migration

9 Conclusions Inhibition of PI3K/AKT pathway with Enzastaurin minimal effect in chondrosarcoma Fyn most important Src family member in chondrosarcoma Dasatinib inhibits migration and overcomes chemoresistance Combination therapy of dasatinib with doxorubicin in high grade chondrosarcoma

Acknowledgements FP7 European Clinical Trials in Rare Sarcomas within an integrated translational trial network EuroBoNet Network of Excellence European network to promote research into uncommon cancers in adults and children: Pathology, Biology and Genetics of Bone Tumours