KCa channel targeting impairs DNA repair and invasiveness of patient‐derived glioblastoma stem cells in culture and orthotopic mouse xenografts which only in part is predictable by KCa expression levels

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Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain‐infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem‐like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal‐to‐proneural mRNA signature of patient derived GSC‐enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IK Ca and BK Ca Ca 2+ ‐activated K + channels. Therefore, we analyzed here the effect of IK Ca ‐ and BK Ca ‐targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC‐derived orthotopic xeno graft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K + channel targeting. As a result, the IK Ca ‐ and BK Ca ‐blocker TRAM‐34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IK Ca ‐ and BK Ca ‐expressing pGSC cultures, respectively. In addition, BK Ca ‐ but not IK Ca ‐blockade slowed‐down gel invasion in vitro. Moreover, systemic administration of TRAM‐34 or paxilline concomitant to fractionated tumor irradiation increased in the xeno graft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that K Ca ‐blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.