The role of extracellular vesicles in acquisition of resistance to therapy in glioblastomas

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 15 months despite standard care therapy consisting of maximal surgical debulking, followed by radiation therapy with concurrent and adjuvant temozolomide treatment. The natural history of GBM is characterized by inevitable recurrence with patients dying from increasingly resistant tumor regrowth after therapy. Several mechanisms including inter- and intratumoral heterogeneity, the evolution of therapy-resistant clonal subpopulations, reacquisition of stemness in glioblastoma stem cells, multiple drug efflux mechanisms, the tumor-promoting microenvironment, metabolic adaptations, and enhanced repair of drug-induced DNA damage have been implicated in therapy failure. Extracellular vesicles (EVs) have emerged as crucial mediators in the maintenance and establishment of GBM. Multiple seminal studies have uncovered the multi-dynamic role of EVs in the acquisition of drug resistance. Mechanisms include EV-mediated cargo transfer and EVs functioning as drug efflux channels and decoys for antibody-based therapies. In this review, we discuss the various mechanisms of therapy resistance in GBM, highlighting the emerging role of EV-orchestrated drug resistance. Understanding the landscape of GBM resistance is critical in devising novel therapeutic approaches to fight this deadly disease.

Keywords: Glioblastoma; extracellular vesicles; radiation; resistance; temozolomide.

Figure 1

Overview of EV-mediated mechanisms of drug resistance. EVs derived from (A) resistant tumor cells and (B) tumor supporting cells transfer genomic and proteomic cargo to glioma treatment sensitive cells, which enhances their acquisition of a resistant phenotype; (C) EVs also function as decoys for antibody-based therapies, leading to the sequestration of anticancer antibodies; (D) EVs package and export drugs out of the cells, reducing its intracellular concentration