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  3. SYK Inhibition Potentiates the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells in Vitro

SYK Inhibition Potentiates the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells in Vitro

  • Cancers (Basel). 2019 Feb 10;11(2):202. doi: 10.3390/cancers11020202.
Conny Tümmler 1,  Gianina Dumitriu 2,  Malin Wickström 3,  Peter Coopman 4,  Andrey Valkov 5,  Per Kogner 6,  John Inge Johnsen 7,  Ugo Moens 8,  Baldur Sveinbjörnsson 9 10
Affiliations

Affiliations

  • 1 Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway. conny.tummler@uit.no.
  • 2 Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway. gianina.dumitriu@uit.no.
  • 3 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Tomtebodav 18A, 17177 Stockholm, Sweden. Malin.Wickstrom@ki.se.
  • 4 IRCM, Inserm U1194, Université Montpellier, ICM, Institut régional du Cancer Montpellier, Campus Val d'Aurelle, 208 Rue des Apothicaires, 34298 Montpellier Cedex 5, France. peter.coopman@inserm.fr.
  • 5 Department of Clinical Pathology, University Hospital of Northern Norway, Sykehusveien 38, 9019 Tromsø, Norway. andrej.yurjevic.valkov@unn.no.
  • 6 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Tomtebodav 18A, 17177 Stockholm, Sweden. Per.Kogner@ki.se.
  • 7 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Tomtebodav 18A, 17177 Stockholm, Sweden. John.Inge.Johnsen@ki.se.
  • 8 Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway. ugo.moens@uit.no.
  • 9 Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Hansine Hansens veg 18, 9019 Tromsø, Norway. baldur.sveinbjornsson@uit.no.
  • 10 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Tomtebodav 18A, 17177 Stockholm, Sweden. baldur.sveinbjornsson@uit.no.
PMID: 30744170 DOI: 10.3390/cancers11020202
Abstract

Neuroblastoma is a malignancy arising from the developing sympathetic nervous system and the most common and deadly Cancer of infancy. New therapies are needed to improve the prognosis for high-risk patients and to reduce toxicity and late effects. Spleen tyrosine kinase (Syk) has previously been identified as a promising drug target in various inflammatory diseases and cancers but has so far not been extensively studied as a potential therapeutic target in neuroblastoma. In this study, we observed elevated Syk gene expression in neuroblastoma compared to neural crest and benign neurofibroma. While Syk protein was detected in the majority of examined neuroblastoma tissues it was less frequently observed in neuroblastoma cell lines. Depletion of Syk by siRNA and the use of small molecule Syk inhibitors significantly reduced the cell viability of neuroblastoma cell lines expressing Syk protein. Moreover, Syk inhibition decreased ERK1/2 and Akt phosphorylation. The Syk Inhibitor BAY 613606 enhanced the effect of different chemotherapeutic drugs. Transient expression of a constitutive active Syk variant increased the viability of neuroblastoma cells independent of endogenous Syk levels. Collectively, our findings suggest that targeting Syk in combination with conventional chemotherapy should be further evaluated as a treatment option in neuroblastoma.

Keywords

combination therapy; neuroblastoma; pediatric cancer; tyrosine kinase.

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