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To date current therapies of glioblastoma multiforme (GBM) are largely ineffective. The induction of apoptosis by an unresolvable unfolded protein response (UPR) represents a potential new therapeutic strategy. Here we tested 12ADT, a sarcoendoplasmic reticulum Ca 2+  ATPase (SERCA) inhibitor, on a panel of unselected patient-derived neurosphere-forming cells and found that GBM cells can be distinguished into “responder” and “non-responder”. By RNASeq analysis we found that the non-responder phenotype is significantly linked with the expression of UPR genes, and in particular  ERN1  (IRE1) and  ATF4 . We also identified two additional genes selectively overexpressed among non-responders,  IGFBP3  and  IGFBP5 . CRISPR-mediated deletion of the  ERN1, IGFBP3, IGFBP5  signature genes in the U251 human GBM cell line increased responsiveness to 12ADT. Remarkably, >65% of GBM cases in The Cancer Genome Atlas express the non-responder ( ERN1, IGFBP3, IGFBP5 ) gene signature. Thus, elevated levels of IRE1α and IGFBPs predict a poor response to drugs inducing unresolvable UPR and possibly other forms of chemotherapy helping in a better stratification GBM patients.

IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells