The Many Facets of Therapy Resistance and Tumor Recurrence in Glioblastoma

Abstract

Glioblastoma (GBM) is the most lethal type of primary brain cancer. Standard care using chemo- and radio-therapy modestly increases the overall survival of patients; however, recurrence is inevitable, due to treatment resistance and lack of response to targeted therapies. GBM therapy resistance has been attributed to several extrinsic and intrinsic factors which affect the dynamics of tumor evolution and physiology thus creating clinical challenges. Tumor-intrinsic factors such as tumor heterogeneity, hypermutation, altered metabolomics and oncologically activated alternative splicing pathways change the tumor landscape to facilitate therapy failure and tumor progression. Moreover, tumor-extrinsic factors such as hypoxia and an immune-suppressive tumor microenvironment (TME) are the chief causes of immunotherapy failure in GBM. Amid the success of immunotherapy in other cancers, GBM has occurred as a model of resistance, thus focusing current efforts on not only alleviating the immunotolerance but also evading the escape mechanisms of tumor cells to therapy, caused by inter- and intra-tumoral heterogeneity. Here we review the various mechanisms of therapy resistance in GBM, caused by the continuously evolving tumor dynamics as well as the complex TME, which cumulatively contribute to GBM malignancy and therapy failure; in an attempt to understand and identify effective therapies for recurrent GBM.

Keywords: Glioblastoma; hypermutation; hypoxia; metabolism; recurrence; resistance; splicing; tumor heterogeneity; tumor microenvironment.

Figure 1

Different transcritptional subtypes of GBM cells and their associated mutations in bold. scRNA seq studies have elucidated three different subtypes of GBM cells namely Proneural (PN), Classical (CL), and Mesenchymal (MES) subtypes manifesting the PDFRA, EGFR and NF1 mutations respectively.

Figure 2

Splicing can be modulated at multiple levels. Pre-splicing, modifying enzymes, like the methyltransferase PRMT5, can be inhibited preventing spliceosome assembly. Core spliceosome components, like SF3B1, can also be inhibited leading to unproductive splicing. Isoform modulation can also be a target of alternative splicing to switch to a less oncogenic protein isoform. Clinicaltrials.gov identifiers (NCT) are included where small molecule inhibitors or modulators are being tested in humans.

Figure 3

Complex pathways underlie the therapeutic resistance of GBM. The decrease of oxygen within in the tumor can facilitate hypoxia-induced signaling which can render cells less sensitive to treatment. Tumor heterogeneity can complicate therapeutic response as not all clones are targeted equally by standard treatments. Immune regulation is severely dampened in GBM, creating a “cold” TME. Splicing changes via RBPs or splicing factors can affect isoform outcome leading to dysregulated AS. Metabolic changes induced by TMZ or RT are able to change metabolism in both the tumor cells as well as the TME, creating a therapeutic-resistant microenvironment. TMZ-induced hypermutation can create a hypermutator state in which patient outcome is correlated with a worse overall survival, as compared to other cancers. Overall, many pathways play a role in GBM therapeutic resistance, and all should be investigated for better second-line treatments. RBPs, RNA binding proteins; AS, Alternative splicing; RBCs, red blood cells, CAFs, cancer-associated fibroblasts.