Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update

Abstract

Gliomas are the most common and challenging malignancies of the central nervous system (CNS), due to their infiltrative nature, tendency to recurrence, and poor response to treatments. Indeed, despite the advances in neurosurgical techniques and in radiation therapy, the modest effects of therapy are still challenging. Moreover, tumor recurrence is associated with the onset of therapy resistance; it is therefore critical to identify effective and well-tolerated pharmacological approaches capable of inducing durable responses in the appropriate patient groups. Molecular alterations of the RTK/PI3K/Akt/mTOR signaling pathway are typical hallmarks of glioma, and several clinical trials targeting one or more players of this axis have been launched, showing disappointing results so far, due to the scarce BBB permeability of certain compounds or to the occurrence of resistance/tolerance mechanisms. However, as RTK/PI3K/mTOR is one of the pivotal pathways regulating cell growth and survival in cancer biology, targeting still remains a strong rationale for developing strategies against gliomas. Future rigorous clinical studies, aimed at addressing the tumor heterogeneity, the interaction with the microenvironment, as well as diverse posology adjustments, are needed-which might unravel the therapeutic efficacy and response prediction of an RTK/PI3K/mTOR-based approach.

Keywords: EGFR; HCGs; PI3K-mTOR; RTKs; glioma.

Figure 1

Representative image of the main signaling pathways that regulate mTOR. mTORC1 is able to capture and transduce signals from different stimuli, such as the presence of growth factors, amino acids, and glucose through the mechanisms indicated. Once activated, mTORC1 promotes cell growth and proliferation, inducing various anabolic processes, including protein synthesis, and inhibiting catabolic processes, such as autophagy. mTORC2, on the other hand, performs an important regulatory function of the cytoskeleton, cell survival, and metabolism and phosphorylates the Akt kinase, determining its activation. This image was created with BioRender software.

Figure 2

EGFR/PI3K/mTOR signaling pathway and inhibitory molecules used in preclinical and clinical studies for glioma therapy. Upon binding to its ligand or genetic alterations, EGFR is activated and triggers a series of cascade reactions. Among these reactions, the phosphorylation and the consequent activation of the ERK pathway and the PI3K/mTOR axis regulate cell growth, proliferation, motility, survival, transcription, and protein synthesis. Many molecules have been developed and employed targeting EGFR, PI3K, and mTOR proteins. Recently, mTOR inhibition by Torin1 and AZD8055 has been shown to mediate EGFR internalization and its delivery to lysosomes in GBM cells [54]. This image was created with BioRender software.