Abstract
Small molecule inhibitors have been investigated in a large set of clinical trials in malignant gliomas. Despite promising preclinical studies, results of pilot trials have been generally disappointing. A deeper understanding of the complex biology of malignant glioma cells, and their adaptation to targeted agents is therefore critical for further therapy development. We analyzed gene expression in 18 short-term serum-free cultures of high-grade gliomas enhanced for brain tumor initiating cells (BTIC) before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Geneset enrichment analysis (GSEA) revealed that some of the regulated patterns are associated to the amino acid metabolism. In gene ontology annotations, additional evidence was raised that ER-stress response signaling which is connected to the amino acid metabolism is induced by Sunitinib. Based on the observation of gene network analysis (STRING) we hypothesize that the central mediator of the integrated stress response ATF4 (activating transcription factor 4) plays an important role in the regulation of the Sunitinib induced expression profiles and probably in the adaptation to treatment conditions. First, we confirmed a concentration dependent induction of ATF4 protein expression in Sunitinib treated BTICs. For further evaluation, we analyzed the expression of ATF4 in paraffin embedded tissue blocks from high grade glioma patients treated with Sunitinib by immunohistochemistry. ATF4 significantly correlated with shorter overall survival from the beginning of Sunitinib treatment. Interestingly, expression data from high grade gliomas retrieved from a public platform (REMBRANDT) revealed that transcription of the ATF4-induced TRB3 pseudokinase is negatively correlated with overall survival independent of treatment. In summary our data suggest that ATF4 expression may be predictive for response to Sunitinib and might also be involved in general resistance mechanisms in high grade gliomas. Further studies are planned to elucidate the induction of apoptosis and autophagy in dependence of ATF4 expression and its contribution to therapy resistance.
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