Table 1.

PI3K/AKT/mTOR pathway in pituitary adenomas.

Study	Country	Clinical Data	Method and Sample	Results
Sajjad et al., 2013 [116]	Poland	53 Pituitary adenomas: 14 GHomas, 33 NFPAs, 6 ACTHomas Male/Female GHomas: 4/10 NFPAs: 21/12 ACTHomas: 2/4 Age: 54.6 ± 15.7	Tissue samples Western blot Primary cell culture	The level of mTOR kinase activity was calculated as pS6rp/elF4E ratio in all tissue samples. GHomas had the highest level of mTOR activity in comparison to NFPA (p = 0.04). The level of mTOR activity did not show any significant correlation with any of the parameters (tumor volume, tumor largest dimension, Knosp’s grading, Ki-67%, and pErk activity). All primary cell culture lines showed mTOR inhibition in response to rapamycin.
Di Pasquale et al., 2018 [121]	Italy	Not applicable	Cell culture (GH3 and GH4C1 rat pituitary adenoma cell lines) GH secretion RNA extraction and qRT-PCR Western blot	GH3 cell viability was significantly induced by IGF1 (+30%; p < 0.01 vs. untreated control cells) and reduced by everolimus and NVP-BEZ235 up to 30% (p < 0.01 vs. untreated control cells). GH4C1 cell viability was not influenced by IGF1 but was significantly reduced by everolimus (−60%; p < 0.01 vs. control treated cells) and by NVP-BEZ235 (−46%; p < 0.01 vs. untreated control cells). IGF1 significantly inhibited GH secretion (−40%; p < 0.01 vs. untreated control cells). IGF1 reduced GH mRNA expression (−37%; p < 0.01 vs. untreated control cells).
Zhu et al., 2021 [119]	China	Not applicable	Rat prolactinoma cell lines (GH3 cells) Western blot Cell counting kit (CCK)-8 assay	ACT001 induced autophagic cell death in cabergoline CAB-resistant GH3 cells by AMPK-mTOR pathway. The cell viability of the CAB + ACT001 group was lower than that of the CAB group (35.30 ± 3.33% vs. 59.63 ± 1.76%, p < 0.001) and ACT001 group (35.30 ± 3.33% vs. 84.10 ± 3.90%, p < 0.001). The number of autophagosomes in the CAB + ACT001 group was significantly higher than that in the CAB group (p < 0.001) and ACT001 group (p < 0.001).
Tang et al., 2019 [118]	China	Not applicable	Cell culture (MMQ cells and GH3 cells) Western blot	Levels of p-AKT (p = 0.0034) and p-mTOR (p = 0.0005) were significantly lower in the group treated by cabergoline than in the control group.
Mangili et al., 2022 [123]	Italy	NF-PitNETs:14 Male/Female: 6/8 Age: 60.7 ± 13.8	Tissue samples Primary cell culture RT-PCR analysis	Everolimus treatment was effective in reducing cell proliferation in 5 out of 14 NF-PitNET primary cultured cells (−39.2 ± 25.8% at 1 nM, p < 0.01 vs. basal). In NF-PitNETs resistant to Everolimus, the coadministration of cabergoline was effective in inhibiting cell proliferation in 7 out of 9 tumors (−31.4 ± 9.9%, p < 0.001 vs. basal).
Jia et al., 2013 [113]	China	95 Pituitary adenomas: NFPAs 59 PRLomas 5, GHomas 8, LHomas 2, FSHomas 2, TSHomas 4, ACTHomas 6, Mixed 9 Male/Female: 51/44 Age: <45 45 >45 50	Tissue samples Quantitative gene transcript analyses	Correlation between RICTOR expression and tumor size, namely p = 0.0012 and p = 0.0055 for tumors 1–2 cm and tumors >3 cm compared with tumors < 1 cm. Higher levels of mTOR were seen in tumors with cystic lesions (p = 0.044). Levels of mTOR were found to be significantly correlated with levels of both RAPTOR (p = 0.000234) and RICTOR (p = 0.0000002). RAPTOR and RICTOR levels were also significantly correlated (p < 0.0000002).
Li et al., 2017 [122]	China	11 Gonadotrophin adenomas Male/Female: 7/4 Age: 43.9 ± 16	Tissue samples RNA-seq analysis qRT-PCR	Genome-wide analysis of lncRNAs and mRNAs obtained from gonadotrophin adenomas. Co-expression involving 126 lncRNAs interacting with 14 mRNAs of the mTOR pathway (PCC > 0.80, p < 0.001), which might promote the pathogenesis of the gonadotrophin tumor.

Healthy controls (HC), real-time polymerase chain reaction (RT-PCR), quantitative polymerase chain reaction (qPCR), western blot (WB), immunohistochemistry (IHC), tissue microarray (TMA), growth hormone-producing pituitary adenoma (GHPA), ACTH-producing pituitary adenoma (ACTHoma), nonfunctional pituitary adenoma (NFPA), nonfunctional pituitary neuroendocrine tumor (NF-PitNET), LHoma (LH-producing pituitary adenoma), FSHoma (FSH-producing pituitary adenoma), TSHoma (TSH-producing pituitary adenoma), PRLoma (PRL-producing pituitary adenoma), phosphorylated-AKT (pAKT), long non-coding RNA (lcnRNA).