Everolimus in pituitary tumor: a review of preclinical and clinical evidence

Abstract

Although pituitary tumors (PTs) are mostly benign, some PTs are characterized by low surgical resection rates, high recurrence rates, and poor response to conventional treatments and profoundly affect patients' quality of life. Everolimus (EVE) is the only FDA-approved mTOR inhibitor, which can be used for oral treatment. It effectively inhibits tumor cell proliferation and angiogenesis. It has been administered for various neuroendocrine tumors of the digestive tract, lungs, and pancreas. EVE not only suppresses the growth and proliferation of APT cells but also enhances their sensitivity to radiotherapy and chemotherapy. This review introduces the role of the PI3K/AKT/mTOR pathway in the development of APTs, comprehensively explores the current status of preclinical and clinical research of EVE in APTs, and discusses the blood-brain barrier permeability and safety of EVE.

Keywords: Everolimus; PI3K/AKT/mTOR; blood-brain barrier; pituitary tumor; safety.

Figure 1

Schematic overview of the PI3K/AKT/mTOR signaling pathway. mTORC1 promotes mRNA translation (A), inhibits autophagy (B), promotes lipid synthesis-related genes and represses expression of apoptosis-related genes (C) through nutrient signals generated by growth factors such as insulin and insulin-like growth factor (D). IGF, insulin-like growth factor; Ptdlns(4,5)P2, phosphatidylinositol-4,5-bisphosphate; Ptdlns(3,4,5)P3, triphosphoinositide; IRS1, insulin receptor substrate 1; SGK, serum- and glucocorticoid-regulated kinase; FOXO, forkhead box protein O; RHEB, Ras homolog enriched in brain; ATG, autophagy-related; ULK1, UNC51-like kinase 1; FIP200, 200 kDa FAK family kinase-interacting protein; eIF, eukaryotic translation initiation factor; 4E-BP1, eIF4E-binding protein 1; S6K1, ribosomal S6 kinase; SKAR, S6K1 Aly/REF-like target; SREBP, sterol regulatory element-binding protein; PPARγ, peroxisome proliferator-activated receptor-γ. [Adapted from Zoncu et al. (139)].