**3.3 Disrupting the PI3K/AKT/mTOR pathway is an attractive therapeutic strategy to inhibit LCs**

There is an enrichment of LCs observed in late-stage OC associated with the up-regulation of the PI3K/AKT/mTOR pathway [37, 93]. Yamaguchi et al.'s study revealed the up-regulation of PI3K in kidney epithelial LCs [44] implicating this pathway as a potential target for LC inhibition. The PI3K/AKT/mTOR signalling pathway mediates major cellular events such as growth, motility, metabolism, and survival [94].

PI3Ks are a group of membrane-associated kinases that form heterodimeric structures comprised of regulatory and catalytic subunits classified based on their structure, regulation and substrates [95]. Class I PI3Ks are hugely implicated in cancer and are comprised of a p85 regulatory and a p110 catalytic subunit [96]. The catalytic subunit in class IA has three variants including p110α, p110β, and p110δ encoded by *PIK3CA*, *PIK3CB* and *PIK3CD* respectively, whilst the catalytic subunit of the only class IB PI3K, p110γ, is produced from *PIK3CG* gene [96]. Class IA PI3Ks are activated via ligand binding to receptor tyrosine kinases (RTKs), while activation IB PI3Ks is mediated by G-protein-coupled receptors (GCPRs) [97]. Upon ligand binding, activated PI3Ks catalyse phosphorylation of phosphatidylinositol (PtdIns) [4, 5] P2 (PIP2) to produce PtdIns [3–5] P3 (PIP3), an event that is inhibited by the tumour suppressor Phosphatase and tensin homologue (PTEN) in normal cells [94]. Following PIP2 to PIP3 conversion, proteins with a PH domain are recruited to the plasma membrane to activate downstream signalling proteins such as AKT, triggering multiple downstream pathways regulating survival, growth and invasion [94, 98]. AKT, also known as protein kinase B (PKB) is the main effector of PI3K and other than direct activation by PI3K, can be activated indirectly by mTOR and phosphoinositide-dependent kinase-1 (PDK1) that phosphorylate AKT at Ser 473 and Tyr 308 residues, respectively [99–101]. A schematic overview of the PI3K/AKT/mTOR pathway is demonstrated in (**Figure 2**).
