PI3K/AKT/mTOR pathway blockade

The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling is one of the critical intracellular pathways that regulates important cell activities, such as cell growth, survival, proliferation, differentiation, metabolism, apoptosis, and angiogenesis.¹⁶⁵ PI3K is plasma membrane-associated lipid kinases, composed of regulatory subunit (PIK3R) and catalytic subunit (PIK3CA) that mediate receptor binding, activation, and localization of the enzyme.¹⁶⁶ In normal conditions, PI3K can be activated by a variety of stimuli, including growth factors, cytokines, and hormones.¹⁶⁷ Activation of AKT regulates a number of downstream targets. mTOR is a serine/threonine protein kinase and the best-described downstream target of AKT, composed of mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2).¹⁶⁸ mTORC1 is sensitive to inhibition by rapamycin, and its analogs and mTORC2 exerts a positive feedback activation on AKT.¹⁶⁹ There are also endogenous negative regulators of the PI3K pathway, such as the tumor suppressor—phosphatase and tensin homologue (PTEN).¹⁷⁰ The PI3K/Akt/mTOR pathway is also involved in cross talk with other signaling pathways, including the Ras/Raf/MEK and estrogen receptor (ER) pathways.¹⁷¹ The overview of the PI3K/AKT/mTOR signaling pathway is included in Fig. ​Fig.1.1. In cancer, this pathway can be aberrantly activated via a number of mechanisms, including loss of tumor-suppressor function, exposure to carcinogens, mutations/amplifications of PI3K, and mutations/amplifications of AKT. The deregulation of the PI3K/ AKT/mTOR pathway occurs in many cancers.^172–174 As for gynecological cancers, this pathway is overactivated in OC (~70%),^175–177 as well as EC and CC.^178–180 In EC, the mutation rates of PI3K and PTEN were high, especially in the POLE subgroup.²⁰ In vitro model of CC, mTOR inhibitors markedly reduced the expression level of HPV E7 protein, inducing apoptosis.¹⁸¹ Based on the preclinical evidence, the PI3K/AKT/mTOR pathway emerges as a potential therapeutic target in cancer, as well as gynecological malignancy.^176,182,183 There are many drugs being tested in each part of this pathway: PI3K inhibitors, mTOR inhibitors, AKT inhibitors, and dual inhibitors on PI3K/mTOR or PI3K/AKT. mTOR inhibitors (everolimus and temsirolimus) and PI3K inhibitors (idelalisib, alpelisib and copanlisib) have been FDA-approved to be effective in the advanced cancer treatment, such as breast cancer, renal cell carcinoma, and lymphoma.¹⁶⁴ Despite there are a number of preclinical/clinical data on PI3K/AKT/mTOR pathway inhibitors, currently there is no FDA-approved indication in gynecological cancers.