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 Netherlands²Dept 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
Intensity Molecules Description
681.09 AKT1 V-AKT murine thymoma viral homolog1
587.329 GSK3β Glycogen synthase kinase 3β
501.354 TTN Titin
446.35 RPS6KA5 Ribosomal protein S6 kinase alpha-5
410.859 FYN FYN oncogene related SRC, FGR, YES
410.859 LCK Lymphocyte 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
