PI3K and cancer: lessons, challenges and opportunities

Abstract

The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.

Figure 1. Targets in the signaling network and their role in tumor biology

This diagram shows a highly simplified scheme of the signaling pathway leading from PI3K to AKT to mTOR. The four isoforms of class I PI3K are shown in dark gray boxes. Blue italics illustrate cancer cell-intrinsic functions of isoforms: p110α is a frequent genetic driver (PIK3CA mutations); basal activity of p110β is implicated in tumors with PTEN loss; p110δ has a fundamental role in survival of normal B cells and malignancies of this lineage. PI3K and mTOR drive tumor metastasis by promoting cell motility and epithelial-mesenchymal transition (EMT). Purple arrows represent cell extrinsic functions of various components in the network. p110α drives angiogenesis. p110γ, p110δ and p110β have important functions in inflammatory cells. p110δ and mTOR control key aspects of adaptive immunity including lymphocyte activation, differentiation and tolerance. Drugs in clinical development that target nodes in this network are listed in Supplementary Table 1.

Figure 2. Complexity, crosstalk and feedback in the PI3K/AKT/mTOR signaling network

(A) The TORC1-TORC2 network and key feedback mechanisms. The mTOR serine-threonine kinase forms two multi-protein complexes whose defining subunits are raptor (TORC1) and rictor (TORC2). TORC2 activity is stimulated by association with ribosomes and by growth factors through a poorly defined mechanism, which may involve PI3K. TORC2 promotes stability and activity of AKT and other kinases including serum- and glucocorticoid-induced kinases (SGKs) and protein kinase C (PKC). TORC1 is a signal integrator whose activity is tuned by diverse inputs. Growth factors, energy sensors and cellular stress converge at the level of the TSC complex (TSC1/TSC2/TBC1D7), a negative regulator of TORC1 with GAP activity towards the Rheb GTPase. Amino acids regulate TORC1 through the Ragulator and GATOR complexes. TORC1 promotes anabolic programs through many substrates, of which three classes are shown: S6 kinases, eukaryotic initiation factor-4E (eIF4E)-binding proteins (4E-BPs), and autophagy regulators (ULK1, etc.). TORC1 activity exerts feedback control on growth factor signaling. One canonical feedback pathway is initiated by S6 kinase-1 (S6K1), a TORC1 substrate, which phosphorylates adaptor proteins of the insulin receptor substrate (IRS) family to attenuate growth factor receptor signaling to PI3K and RAS. In parallel, TORC1 suppresses growth factor receptor signaling by phosphorylating the GRB10 adaptor protein. AKT activity triggers a feedback mechanism that suppresses growth factor receptor expression and signaling. Through phosphorylation and inactivation of Forkhead Box Subgroup O (FOXO) transcription factors, active AKT reduces the transcription of FOXO target genes including several growth factor receptors. (B) Redundancy and feedback between the RAS-RAF-MEK-ERK and PI3K/AKT/mTOR signaling networks. ERK and downstream kinase RSK can compensate for AKT in the activation of TORC1 via inhibitory TSC phosphorylation; GSK3 and AMPK phosphorylation of TSC2 increase its ability to suppress TORC1 activity. MNK kinases phosphorylate eIF4E to provide a distinct signal to increase cap-dependent translation. ERK and mTOR independently promote accumulation of MYC oncoproteins. Mutual feedback inhibition is a feature of the two pathways: MEK activity suppresses PI3K signaling by promoting PTEN membrane localization, while TORC1 activity suppresses RAS activation through mechanisms shown in Figure 3.

Figure 3. Two arguments for combining TKIs with PI3K/AKT/mTOR inhibitors

Left: In cancers driven by activated tyrosine kinases, TKI resistance can develop through alternative pathways that maintain PI3K signaling such as compensatory growth factor (GF) receptors, PTEN loss, PIK3CA mutation or RAS activation. Combined targeting of PI3K can prevent or overcome drug resistance. Right: In cancers driven by lesions in PI3K or PTEN, inhibiting PI3K or AKT or TORC1/TORC2 can cause elevated GF receptor signaling through FOXO-dependent gene expression. Adding a TKI can ameliorate this compensatory signaling mechanism.

Figure 4. Rationale for BCL2 antagonist combination

The balance of pro-survival and proapoptotic BCL2 family members at the mitochondria is a primary factor controlling cell survival versus apoptosis. PI3K/AKT/mTOR signaling suppresses expression and activity of multiple pro-apoptotic proteins (i.e. BAD, BIM, PUMA, and death receptors) and can increase expression of pro-survival factors (MCL-1). However, PI3K/AKT/mTOR inhibition does not necessarily tip the balance towards apoptosis. Combining with small molecule antagonists of pro-survival proteins (BCL2, BCL-X_L) increases mitochondrial “priming” for death, lowering the threshold for apoptosis induction by PI3K/AKT/mTOR inhibitors.