Sensitivity to <i>BUB1B</i> Inhibition Defines an Alternative Classification of Glioblastoma

Abstract

Glioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule <i>BUB1B</i> may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates requires <i>BUB1B</i> to suppress lethal kinetochore-microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes, and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to <i>BUB1B</i> inhibition. Applying this framework to tumor expression data from patients, we stratified tumors into BUB1B-sensitive (BUB1B^S) or BUB1B-resistant (BUB1B^R) subtypes. Through this effort, we found that BUB1B^S patients have a significantly worse prognosis regardless of tumor development subtype (i.e., classical, mesenchymal, neural, proneural). Functional genomic profiling of BUB1B^R versus BUB1B^S isolates revealed a differential reliance of genes enriched in the BUB1B^S classifier, including those involved in mitotic cell cycle, microtubule organization, and chromosome segregation. By comparing drug sensitivity profiles, we predicted BUB1B^S cells to be more sensitive to type I and II topoisomerase inhibitors, Raf inhibitors, and other drugs, and experimentally validated some of these predictions. Taken together, the results show that our BUB1B^R/S classification of GBM tumors can predict clinical course and sensitivity to drug treatment. <i>Cancer Res; 77(20); 5518-29. ©2017 AACR</i>.