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

Publication Title

Sci Rep

Authors

Jeffrey J Rodvold
Su Xian
Julia Nussbacher
Brian Tsui
T Cameron Waller
Stephen C Searles
Alyssa Lew
Pengfei Jiang, Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USA
Ivan Babic, Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USA
Natsuko Nomura, Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USAFollow
Jonathan H Lin
Santosh Kesari, Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute/Pacific Neuroscience Institute, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USAFollow
Hannah Carter
Maurizio Zanetti

Document Type

Article

Publication Date

5-20-2020

Abstract

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 Ca2+ 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.

Clinical Institute

Neurosciences (Brain & Spine)

Specialty/Research Institute

Neurosciences

Specialty/Research Institute

Pathology & Laboratory Medicine