Targeting the PI3K/AKT/mTOR Pathway in Cancer Cells

Abstract

The PI3K/AKT/mTOR constitutes an important pathway downstream of growth factor tyrosine kinase receptors, thus regulating a plethora of biological processes as angiogenesis, proliferation, metabolism, survival, and differentiation [3]. Accumulating evidences indicate,

Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges

“…Phosphorylation of protein kinase B (Akt) and other AGC-family kinases (e.g., serum- and glucocorticoid-induced protein kinase 1, SGK1; protein kinases C, PKC) has been linked with mTORC2 activation, with important consequences on cell survival, cytoskeleton organization, and cycle progression [ 14 , 20 , 21 ]. Interestingly, Akt appears to have a complex dual role on mTOR, being both an (i) upstream regulator of mTORC1 (indirect activation through phosphorylation and inactivation of TSC1/TSC2 complex, who constitutively suppress mTORC1 activity through Rheb GTPase inhibition) and a (ii) downstream target of mTORC2 [ 10 , 22 ]. The activity of the two complexes is finely and mutually tuned through some feedback circuits promoted not only by upstream regulators of mTORC1 (e.g., Akt) but also by other downstream effectors of mTORC1, such as the p70S6K1 [ 23 – 25 ].…”

“…Hence, impairments of constitutive feedback mechanisms and unexpected mTOR hyperactivation are particularly relevant when mTOR signaling modulation is envisaged. In this regard, the fact that PI3K/Akt/mTOR pathway critically regulates a plethora of physiological processes that become deregulated in a wide spectrum of pathologic conditions prompt the design of several pharmacological agents that target distinct components of this signaling cascade, as outlined in Section 3 [ 22 , 26 – 28 ].…”

“…The recent breathtaking advances in up- and downstream targets of mTOR, reciprocal feedback mechanistic loops, and mutational loss-of-function in mTOR key components (e.g., TSC1/2, PIK3CA, and Akt), the most common cause of mTOR signaling hyperactivity, provided new rationales for translating the mTOR basic science to the clinic. In fact, pharmaceutical companies have discovered impressive arrays of small molecules targeting PI3K/Akt/mTOR cascade elements which are currently undergoing evaluation in preclinical and clinical studies mainly in cancer and transplantation, even though mTOR inhibitors are being also considered for other pathological conditions such as rheumatoid arthritis, atherosclerosis and a wide spectrum of neurologic disorders where aberrant mTOR pathway activity is consistently observed [ 22 , 27 , 28 , 32 ]. Herein, it will be focused on the different classes of mTOR inhibitors currently undergoing preclinical/clinical studies aimed at providing new pharmacological agents with increased efficacy and a lower side effect profile.…”

“…The fact that rapamycin has limited bioavailability led to the development of semisynthetic analogs, named rapalogues, with superior aqueous solubility and improved pharmacokinetic properties. Examples of this first-generation of mTOR inhibitors are temsirolimus (CCI-779), everolimus (RAD001), and ridaforolimus/deforolimus (MK-8669/AP23573) who share a central macrolide chemical structure yet differ in the functional groups added at C40 that significantly alter bioavailability, half-life, and administration routes (oral versus intravenous) [ 22 ]. In contrast with everolimus and ridaforolimus, temsirolimus is a prodrug that requires removal of the dihydroxymethyl propionic acid ester group after administration, becoming sirolimus in its active form [ 36 ].…”

“…Rapalogues exhibit a safe toxicity profile, with side effects such as skin rashes and mucositis being dose-dependent. Other symptoms described are fatigue, anemia, neutropenia, and metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, and hyperglycemia [ 22 ]. In this regard, it should be highlighted that rapamycin prevented insulin-mediated suppression of hepatic gluconeogenesis and impaired in vitro basal and insulin-stimulated glucose uptake in adipocytes from human donors [ 37 , 38 ].…”