Kinome profiling of myxoid liposarcoma reveals NF-kappaB-pathway kinase activity and casein kinase II inhibition as a potential treatment option.
BACKGROUND
Myxoid liposarcoma is a relatively common malignant soft tissue tumor, characterized by a (12;16) translocation resulting in a FUS-DDIT3 fusion gene playing a pivotal role in its tumorigenesis. Treatment options in patients with inoperable or metastatic myxoid liposarcoma are relatively poor though being developed and new hope is growing.


RESULTS
Using kinome profiling and subsequent pathway analysis in two cell lines and four primary cultures of myxoid liposarcomas, all of which demonstrated a FUS-DDIT3 fusion gene including one new fusion type, we aimed at identifying new molecular targets for systemic treatment. Protein phosphorylation by activated kinases was verified by Western Blot and cell viability was measured before and after treatment of the myxoid liposarcoma cells with kinase inhibitors. We found kinases associated with the atypical nuclear factor-kappaB and Src pathways to be the most active in myxoid liposarcoma. Inhibition of Src by the small molecule tyrosine kinase inhibitor dasatinib showed only a mild effect on cell viability of myxoid liposarcoma cells. In contrast, inhibition of the nuclear factor-kappaB pathway, which is regulated by the FUS-DDIT3 fusion product, in myxoid liposarcoma cells using casein kinase 2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) showed a significant decrease in cell viability, decreased phosphorylation of nuclear factor-kappaB pathway proteins, and caspase 3 mediated apoptosis. Combination of dasatinib and TBB showed an enhanced effect.


CONCLUSIONS
Kinases associated with activation of the atypical nuclear factor-kappaB and the Src pathways are the most active in myxoid liposarcoma in vitro and inhibition of nuclear factor-kappaB pathway activation by inhibiting casein kinase 2 using TBB, of which the effect is enhanced by Src inhibition using dasatinib, offers new potential therapeutic strategies for myxoid liposarcoma patients with advanced disease.
Willems
Stefan M
SM
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Schrage
Yvonne M
YM
Bruijn
Inge H Briaire-de
IH
Szuhai
Karoly
K
Hogendoorn
Pancras C W
PC
Bovée
Judith V M G
JV
D047390:Casein Kinase II / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells; D007621:Karyotyping; D018208:Liposarcoma, Myxoid / Q000188:drug therapy / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use
C405354:4,5,6,7-tetrabromobenzotriazole; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D014230:Triazoles; D047390:Casein Kinase II; D000069439:Dasatinib