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