Pharmacologic Differentiation of Drugs Targeting the PI 3K‐ AKT ‐m TOR Signaling Pathway

Abstract

Phosphoinositide 3-kinase (PI3K) and its downstream signaling through AKT and mammalian target of rapamycin (mTOR) govern diverse physiological and disease-related processes. The pathobiology of the PI3K-AKT-mTOR signaling pathway is reviewed in detail in a separate chapter entitled Principles of PI3K Biology and its Role in Cancer . Briefly, class I PI3K has four catalytic subunits: p110α, p110β, and p110δ, which link PI3K activity to tyrosine kinases, and p110γ, which is associated with G-protein-coupled receptors. The α and β isoforms are ubiquitously expressed in most human tissues. The γ and δ isoforms are predominantly expressed in hematopoietic cells. The functional roles of the PI3K isoforms have been extensively characterized in genetic knockout and mutant mouse models (previously reviewed by Vanhaesebroeck et al. 2005). These studies elucidated the immunological and metabolic changes related to each isoform, including regulation of insulin signaling via the α isoform (Knight et al. 2006) platelet adhesion and aggregation via the β isoform (Garcia et al. 2010) innate immune response and macrophage polarization via the γ isoform (Kaneda et al. 2016) and B-cell development and maintenance of mature B-cell survival via the δ isoform (Srinivasan et al. 2009). Notably, the γ- and δ isoforms have complementary and overlapping roles in T-cell development, differentiation, and activity. Genetic models have demonstrated reduced thymocyte survival and defective cytokine production from stimulated T-cells of PI3Kγ null mice (PI3Kγ-/-) (Sasaki et al. 2000) impaired antigen-mediated T-cell activation in PI3Kδ kinase-inactive mice (PI3Kδ D910A/D910A ) (Okkenhaug et al. 2002) and decreased early T-cell development in PI3Kγ/δ double knockout mice (Webb et al. 2005). The differential tissue expression and distinct functional roles of the isoforms correlate with activity and safety profiles of PI3K inhibitors in the clinic (Lampson and Brown 2021). Some cancer cells hijack the PI3K signaling pathway for tumorigenesis. Solid tumors frequently utilize genetic mechanisms that upregulate PI3K signaling, which include activating mutations in the gene encoding PI3Kα ( PIK3CA ) and deletion or inactivating mutations in PTEN , an antagonist of PI3K signaling (Figure 6.1) (Lawrence et al. 2014; Samuels et al. 2004). Less commonly, activating mutations in AKT1 (Carpten et al. 2007) and MTOR (Grabiner et al. 2014) and inactivating mutations in tuberous sclerosis complex genes ( TSC) have been reported (Inoki et al. 2005). Unlike solid tumors, lymphoid malignancies infrequently exhibit genetic activation of the PI3K signaling pathway. PI3KCA mutations are rare, although PTEN inactivation may occur in lymphoma due to deletion or mutations of the gene (Chapuy et al. 2018; Schmitz et al. 2012) or functional suppression of PTEN activity through the oncogenic miR-17–92 cluster (Dal Bo et al. 2015). Constitutive upregulation of PI3K signaling in B-cell lymphoma is predominantly driven by increased B-cell receptor (BCR) signaling (Ahn and Brown 2021). PI3K is part of the BCR signaling complex recruited after phosphorylation of the surface BCR. In particular, the δ isoform has a critical role in B-cell lymphoma by being involved in both tonic and chronic activated BCR signaling. PI3K signaling itself can also maintain mature B-cell survival independent of BCR signaling, a finding supported by successful rescue of BCR-ablated B-cells with constitutive activation of PI3K or PTEN knockout in vivo (Srinivasan et al. 2009). Conversely, genetic inactivation of PI3Kδ causes severe reduction of B-cell numbers and antigen-dependent BCR signaling, which underscores the crosstalk between PI3K and BCR signaling pathways (Okkenhaug et al. 2002). The central role of PI3Kδ in normal B-cell development and tumorigenesis makes it a compelling therapeutic target in lymphoma. Targeting additional PI3K isoforms has biological and clinical relevance to selected lymphoma subtypes. PI3Kα is genetically activated in a subset of mantle cell lymphoma (MCL)ntagonist of PI3K signal-cell lymphoma (DLBCL) (Abubaker et al. 2007; Psyrri et al. 2009). In T-cell lymphoma, PI3Kδ and PI3Kγ are the primary therapeutic targets due to their known roles in the regulation of T-cell function and chemotaxis (Kaneda et al. 2016; Sasaki et al. 2000). Dual inhibition of the γ and δ isoforms in T-cell lymphoma cell lines with duvelisib led to greater cell killing than sole inhibition of PI3Kδ or the use of the pan-PI3K inhibitor copanlisib, which has less potent activity against PI3Kγ compared to other isoforms (Horwitz et al. 2018). Clinical experiences with PI3K and mTOR inhibitors are discussed in other chapters. Here, we address the pharmacologic properties of molecules targeting the PI3K-AKT-mTOR signaling pathway and their clinical relevance.