Journal Article

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

Carter, Hannah, Jiang, Pengfei, Nomura, Natsuko, Cameron Waller, T., Xian, Su, Rodvold, Jeffrey J., Tsui, Brian, Babic, Ivan, Zanetti, Maurizio, Nussbacher, Julia, Searles, Stephen C., Lew, Alyssa, Lin, Jonathan H., Kesari, Santosh

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 45 / 45/77 / 631/67/1922 / 692/4028/67/1922 / Adenosine triphosphatase / Adult / Apoptosis / Apoptosis - drug effects / Brain - pathology / Brain - surgery / Brain cancer / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Brain Neoplasms - mortality / Brain Neoplasms - surgery / Ca2+-transporting ATPase / Calcium / Cancer therapies / Cell Line, Tumor / Chemotherapy / CRISPR / Cytotoxicity / Drug Resistance, Neoplasm - genetics / Endoplasmic reticulum / Endoplasmic Reticulum Stress - drug effects / Endoribonucleases - genetics / Endoribonucleases - metabolism / Gene Expression Regulation, Neoplastic / Genes / Genomes / Glioblastoma - drug therapy / Glioblastoma - genetics / Glioblastoma - mortality / Glioblastoma - surgery / Glioblastoma cells / Humanities and Social Sciences / Humans / Hypoxia / Insulin-Like Growth Factor Binding Protein 3 - genetics / Insulin-Like Growth Factor Binding Protein 3 - metabolism / Insulin-Like Growth Factor Binding Protein 5 - genetics / Insulin-Like Growth Factor Binding Protein 5 - metabolism / Insulin-like growth factor-binding protein 3 / Insulin-like growth factor-binding protein 5 / Insulin-like growth factors / Kinases / multidisciplinary / Mutation / Patients / Phenotypes / Primary Cell Culture / Progression-Free Survival / Prostate / Protein folding / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / RNA-Seq / Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors / Science / Science (multidisciplinary) / Signal Transduction - genetics / Spheroids, Cellular / Thapsigargin - analogs & derivatives / Thapsigargin - pharmacology / Thapsigargin - therapeutic use / Tumor Cells, Cultured / Unfolded Protein Response - drug effects