The Role of Activation of PI3K/AKT/mTOR and RAF/MEK/ERK Pathways in Aggressive Pituitary Adenomas—New Potential Therapeutic Approach—A Systematic Review

Abstract

Pituitary tumors (PT) are mostly benign, although occasionally they demonstrate aggressive behavior, invasion of surrounding tissues, rapid growth, resistance to conventional treatments, and multiple recurrences. The pathogenesis of PT is still not fully understood, and the factors responsible for its invasiveness, aggressiveness, and potential for metastasis are unknown. RAF/MEK/ERK and mTOR signaling are significant pathways in the regulation of cell growth, proliferation, and survival, its importance in tumorigenesis has been highlighted. The aim of our review is to determine the role of the activation of PI3K/AKT/mTOR and RAF/MEK/ERK pathways in the pathogenesis of pituitary tumors. Additionally, we evaluate their potential in a new therapeutic approach to provide alternative therapies and improved outcomes for patients with aggressive pituitary tumors that do not respond to standard treatment. We perform a systematic literature search using the PubMed, Embase, and Scopus databases (search date was 2012–2023). Out of the 529 screened studies, 13 met the inclusion criteria, 7 related to the PI3K/AKT/mTOR pathway, and 7 to the RAF/MEK/ERK pathway (one study was used in both analyses). Understanding the specific factors involved in PT tumorigenesis provides opportunities for targeted therapies. We also review the possible new targeted therapies and the use of mTOR inhibitors and TKI in PT management. Although the RAF/MEK/ERK and PI3K/AKT/mTOR pathways play a pivotal role in the complex signaling network along with many interactions, further research is urgently needed to clarify the exact functions and the underlying mechanisms of these signaling pathways in the pathogenesis of pituitary adenomas and their role in its invasiveness and aggressive clinical outcome.

Current Insights in Prolactin Signaling and Ovulatory Function in Health and Disease

“…The lack of a physical association with STAT5a, as a result of STAT5 blocking (marked with crossed red lines), may redirect to signaling via RUSH/SMARCA3 (red) with gene regulation mainly through chromatin remodeling. The presence of transcription factors RUSH-1α and RUSH-1β, as well as SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A, member 3 (SMARCA3) in both cytoplasm and nucleus, suggests their bidirectional passage across the nuclear membrane (marked with a double-sided arrow with a dotted line) [78].…”

Current Insights in Prolactin Signaling and Ovulatory Function

“…Next, the tyrosine-phosphorylated STAT complex dissociates from the receptor, dimerizes, and translocates into the nucleus, where it binds to the promoters of target genes. Although the JAK/STAT pathway is considered one of the major downstream pathways for cytokine receptor signaling, PRL also activates ❷ the Ras kinase/Raf kinase/mitogen-activated protein kinase/extracellular signal-regulated kinase ½ (Ras/Raf/MAPK/ERK1/2) pathway [77,78] and ❸ the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3-Kinase/AKT/mTOR) [78,79] downstream signaling pathway. In addition, in the absence of a physical association with STAT5a, ❹ signaling through the transcription factors RUSH-1α, RUSH-1β, and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A, member 3 (RUSH/SMARCA3), have been identified (Figure 3) [80].…”

Hotspots of Somatic Genetic Variation in Pituitary Neuroendocrine Tumors

“…Via the phosphorylation of RPS6KA1, ERK1 and 2 also activate the transcription factor cAMP response element-binding protein (CREB). The activation of this pathway leads to tissue-specific molecular consequences, although in the pituitary gland and in many other tissues it results in increased cell proliferation and survival [18,23,58,59]. In corticotroph cells, this pathway also activates POMC transcription, although the membrane receptor triggering this response in physiological conditions and in corticotropinomas remains unclear [40].…”