Aberrant Notch signaling in gliomas: a potential landscape of actionable converging targets for combination approach in therapies resistance

The current therapeutic protocols and prognosis of gliomas still depend on clinicopathologic and radiographic characteristics. For high-grade gliomas, the standard of care is resection followed by radiotherapy plus temozolomide chemotherapy. However, treatment resistance develops due to different mechanisms, among which is the dynamic interplay between the tumor and its microenvironment. Different signaling pathways cause the proliferation of so-called glioma stem cells, a minor cancer cell population with stem cell-like characteristics and aggressive phenotype. In the last decades, numerous studies have indicated that Notch is a crucial pathway that maintains the characteristics of resistant glioma stem cells. Data obtained from preclinical models indicate that downregulation of the Notch pathway could induce multifaceted drug sensitivity, acting on the expression of drug-transporter proteins, inducing epithelial–mesenchymal transition, and shaping the tumor microenvironment. This review provides a brief overview of the published data supporting the roles of Notch in drug resistance and demonstrates how potential novel strategies targeting Notch could become an efficacious action to improve the therapy of high-grade glioma to overcome drug resistance.