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    • AKT activity is also self

    2024-03-14

    AKT activity is also self-limiting through its substrate GSK3β; the kinase activity of which is negatively regulated by AKT phosphorylation (Fig. 3; Li, Liu, & Gao, 2009). GSK3β activation results in phosphorylation and subsequent ubiquitin mediated degradation of PHLPP (Li et al., 2009). AKT activation therefore results in GSK3β inactivation and high levels of PHLPP, which in turn, puts the brakes on the AKT signalling pathway. Opposing the above mechanisms that limit the activity of the PI3K/AKT pathway, AKT inhibition results in up-regulation of RTKs, in part through loss of mTORC1 signalling, but also due to FOXO-dependent transcriptional increases in RTK expression (Chandarlapaty et al., 2011). This up-regulation of upstream pathway components in part will compensate for pharmacological inhibition of more downstream players and has been shown to contribute to resistance to AKT inhibitors (Garrett, Olivares, et al., 2011). In the context of normal growth factor signalling, it's easy to appreciate why it's advantageous that in ‘times of plenty’, chronic activation of mTORC1, leads to attenuation of AKT signalling (Manning, 2004). As discussed below, multiple components of the PI3K pathway are mutated or deleted in cancer 7ACC1 and the level of the aberration within the pathway will have profoundly different effects on AKT activity depending on whether or not the negative regulatory feedback loops are intact. Equally, chronic vs acute inhibition of the pathway may result in very different signalling patterns. This makes targeting the pathway a significant challenge in oncology and also has implications for dosing schedules of AKT inhibitors.
    AKT activation in cancer The PI3K/AKT pathway is the most commonly disrupted signalling pathway in human cancers (Millis, Ikeda, Reddy, Gatalica, & Kurzrock, 2016). PI3K/AKT pathway aberrations have been identified in up to 40% of all tumour types, with PTEN loss by immunohistochemistry occurring most frequently (30%), followed by mutations in PIK3CA (13%), PTEN (6%) and AKT (1%; Millis et al., 2016). Whilst activating AKT mutations is relatively uncommon, AKT activation can arise as a result of several other genomic aberrations.
    The clinical development of AKT inhibitors Inhibiting PI3K/AKT signalling has long been an attractive therapeutic approach in oncology. Numerous compounds that inhibit the pathway at all levels are now in clinical development, including those targeting AKT (Yap et al., 2008). AKT inhibitors fall predominantly into two separate classes. Allosteric inhibitors of the AKT PH-domain prevent localisation of AKT to the plasma membrane, thereby blocking AKT phosphorylation and activation. The second class of inhibitors comprise ATP-competitive inhibitors of AKT, of which there are several in the early stages of clinical development (Table 2).
    Future directions and conclusions AKT remains a central player in the PI3K-AKT signalling network and promising data from a number of phase II combination trials look set to pave the way for phase III studies and hopefully, clinical registration of some these compounds. Patient selection remains key, with AKT1E17K looking like a particularly strong biomarker predictive of response to AZD5363 monotherapy. A basket trial approach to clinical trial design is becoming increasingly popular and suits collections of low frequency, but high potency mutations such as AKT1E17K. Although potentially slow to complete, the clinical impact for patients harbouring such mutations should not deter licensing of compounds for such niche tumour populations. The presence of AKT1E17K and other genetic aberrations (such as activating PIK3CA mutations and PTEN loss) needs to be put in molecular context however as co-activation of other pro-survival pathways is likely to require combination treatment strategies as demonstrated with AKT and MEK inhibition. Other potential biomarkers such as the RAS pathway signature score and proteomic signatures predictive of response to AKT inhibitors attempt to look beyond the PI3K/AKT pathway itself and should be explored further (Cheraghchi-Bashi et al., 2015, Loboda et al., 2010).