Advancements, Challenges, and Future Directions in Tackling Glioblastoma Resistance to Small Kinase Inhibitors

SIMPLE SUMMARY: Drug resistance is a major issue in brain tumor therapy. Despite novel promising therapeutic approaches, glioblastoma (GBM) remains refractory in showing beneficial responses to anticancer agents, as demonstrated by the failure in clinical trials of small kinase inhibitors. One of the reasons may lie in the development of different types of drug resistance mechanisms derived from the intrinsic heterogeneous nature of GBM. Obtaining insights into these mechanisms could improve the management of the clinical intervention and monitoring. Such insights could be achieved with the improvement of preclinical in vitro models for studying drug resistance. ABSTRACT: Despite clinical intervention, glioblastoma (GBM) remains the deadliest brain tumor in adults. Its incurability is partly related to the establishment of drug resistance, both to standard and novel treatments. In fact, even though small kinase inhibitors have changed the standard clinical practice for several solid cancers, in GBM, they did not fulfill this promise. Drug resistance is thought to arise from the heterogeneity of GBM, which leads the development of several different mechanisms. A better understanding of the evolution and characteristics of drug resistance is of utmost importance to improve the current clinical practice. Therefore, the development of clinically relevant preclinical in vitro models which allow careful dissection of these processes is crucial to gain insights that can be translated to improved therapeutic approaches. In this review, we first discuss the heterogeneity of GBM, which is reflected in the development of several resistance mechanisms. In particular, we address the potential role of drug resistance mechanisms in the failure of small kinase inhibitors in clinical trials. Finally, we discuss strategies to overcome therapy resistance, particularly focusing on the importance of developing in vitro models, and the possible approaches that could be applied to the clinic to manage drug resistance.