Kinome Profiling of Chondrosarcoma Reveals Src-Pathway Activity and Dasatinib as Option for Treatment

Abstract

Chondrosarcomas are notorious for their resistance to conventional chemotherapy and radiotherapy, indicating there are no curative treatment possibilities for patients with inoperable or metastatic disease. We therefore explored the existence of molecular targets for systemic treatment of chondrosarcoma using kinome profiling. Peptide array was performed for four chondrosarcoma cell lines and nine primary chondrosarcoma cultures with GIST882, MSCs, and colorectal cancer cell lines as controls. Activity of kinases was verified using immunoblot, and active Src-and plateletderived growth factor receptor (PDGFR) signaling were further explored using imatinib and dasatinib on chondrosarcoma in vitro. The AKT1/GSK3B pathway was clearly active in chondrosarcoma. In addition, the PDGFR pathway and the Src kinase family were active. PDGFR and Src kinases can be inhibited by imatinib and dasatinib, respectively. Although imatinib did not show any effect on chondrosarcoma cell cultures, dasatinib showed a decrease in cell viability at nanomolar concentrations in seven of nine chondrosarcoma cultures. However, inhibition of phosphorylated Src (Y419) was found both in responsive and nonresponsive cells. In conclusion, using kinome profiling, we found the Src pathway to be active in chondrosarcoma. Moreover, we showed in vitro that the inhibitor of the Src pathway, dasatinib, may provide a potential therapeutic benefit for chondrosarcoma patients who are not eligible for surgery. [Cancer Res 2009;69(15):6216-22]

Functional Profiling of Receptor Tyrosine Kinases and Downstream Signaling in Human Chondrosarcomas Identifies Pathways for Rational Targeted Therapy

“…NRAS mutation analysis in chondrosarcoma clinical samples block of cell growth suggests that other parallel pathways are also likely to be important. Consistent with our data showing RTK activation, strong and common phosphorylation of the downstream signaling proteins AKT, MEK, and S6 kinase was previously shown using kinase substrate peptide arrays and extracts from chondrosarcoma cell lines and primary cultures (35). Here, we have linked RTK activation in chondrosarcoma cells to PI3K/AKT/mTOR signaling by showing that RTK inhibitors suppress AKT and S6 phosphorylation.…”

SRC Signaling Is Crucial in the Growth of Synovial Sarcoma Cells

“…Effectivity of dasatinib has previously been shown for cells derived from solid tumors as well, including mesenchymal neoplasias, such as GIST and chondrosarcoma (34,35). In chondrosarcoma, growth effects observed upon treatment with dasatinib were not consistently associated with diminished p-(Tyr416)-SRC levels, which makes SRC-independent modes of action probable (35). In contrast, in synovial sarcomas, dephosphorylation of SRC and its targets was a consistent feature detectable upon treatment with dasatinib.…”

“…A role for dasatinib is clinically wellestablished in the treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), in which the substance inhibits Abl kinases (32,33). Effectivity of dasatinib has previously been shown for cells derived from solid tumors as well, including mesenchymal neoplasias, such as GIST and chondrosarcoma (34,35). In chondrosarcoma, growth effects observed upon treatment with dasatinib were not consistently associated with diminished p-(Tyr416)-SRC levels, which makes SRC-independent modes of action probable (35).…”

The importance of Src signaling in sarcoma

“…Several studies have demonstrated the therapeutic benefit of dasatinib in preventing the growth and metastasis of sarcomas. In osteosarcoma cell lines, wound-healing, cell migration and TUNEL assays indicated that dasatinib may block cell motility and invasion, and induce apoptosis (45,73). In chondrosarcoma, dasatinib was also capable of decreasing tumor growth, however, it was unable to reduce invasion (73).…”