Differential Effects of PI3K and Dual PI3K/mTOR Inhibition in Rat Prolactin-Secreting Pituitary Tumors

Abstract

Aggressive pituitary tumors are rare but difficult to manage, as there is no effective chemotherapy to restrict their growth and cause their shrinkage. Within these tumors, growth-promoting cascades, like the PI3K/mTOR pathway, appear to be activated. We tested the efficacy of two inhibitors of this pathway, NVP-BKM120 (Buparlisib; pan-PI3K) and NVP-BEZ235 (dual PI3K/mTOR), both in vitro on immortalized pituitary tumor cells (GH3) and on primary cell cultures of human pituitary tumors and in vivo on a rat model of prolactin (PRL) tumors (SMtTW3). In vitro, NVP-BEZ235 had a potent apoptotic and cytostatic effect that was characterized by decreased cyclin D/E and Cdk4/2 protein levels and subsequent accumulation of cells in G 1 . In vivo, the effect was transient, with a decrease in mitotic index and increase in apoptosis; long-term treatment had no significant inhibitory effect on tumor growth. In contrast, while NVP-BKM120 had little effect in vitro, it dramatically limited tumor growth in vivo. Increased Akt phosphorylation observed only in the NVP-BEZ235-treated tumors may explain the differential response to the two inhibitors. Primary cell cultures of human PRL pituitary tumors responded to NVP-BEZ235 with reduced cell viability and decreased hormone secretion, whereas NVP-BKM120 had little effect. Altogether, these results show a potential for PI3K inhibitors in the management of aggressive pituitary tumors.

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

“…Preclinical and clinical studies suggest that new targeted therapies may be useful for controlling pituitary tumour growth (147,148,149,150,151). However, everolimus was tried in 5 patients with aggressive pituitary tumours or carcinomas without success (44,152).…”

Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer

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Exploring the Role of Novel Medical Therapies for Aggressive Pituitary Tumors: A Review of the Literature—“Are We There Yet?”

“…The dual mTOR/PI3K inhibitor NVP-BEZ235 reduces cell proliferation and promotes cell death in rat non-functioning pituitary adenomas in vitro and in vivo [84], in growth hormone-secreting GH3 cell lines in vitro, and in primary cell cultures of human prolactinomas [85]. The pan-PI3K inhibitor NVP-BKM120 (Buparlisib) has demonstrated no significant effect on GH3 cells in vitro but did reduce the tumor volume, prolactin secretion, and mitotic index in rat models of prolactin tumors in vivo [85]. Synergies may also be effective.…”