Resistance to Spindle inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence

While mitotic spindle inhibitors specifically kill proliferating tumor cells without the toxicities of microtubule poisons, resistance has limited their clinical utility. Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of STAT3. Furthermore, these senescent cells expand the repertoire of resistant cells by secreting an array of factors, including TGFb, which induce proliferating cells to exit mitosis and become quiescent—a state that is also insensitive to spindle inhibitors. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. We have incorporated our results into a model that explains how STAT3 and therapy induced senescence combine to drive resistance, which can provide insight into how to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma. Overall design: We generated mouse glioma cell lines with acquired resistance to Ispinesib, Alisertib or Volasertib in order to explore mechanisms of resistance to this class of spindle inhibitors and identify mechanisms of overcoming it. We obtained transcriptomic data from three independently-derived cell lines from each drug treatment using RNAseq. We identified key common pathways that are upregulated in the resistant cells using differential gene expression analysis and GSEA.