At a crossroads: how to translate the roles of PI3K in oncogenic and metabolic signalling into improvements in cancer therapy

Abstract

Numerous agents targeting various phosphatidylinositol 3-kinase (PI3K) pathway components, including PI3K, AKT and mTOR, have been tested in oncology clinical trials, resulting in regulatory approvals for the treatment of selected patients with breast cancer, certain other solid tumours or particular haematological malignancies. However, given the prominence of PI3K signalling in cancer and the crucial role of this pathway in linking cancer growth with metabolism, these clinical results could arguably be improved upon. In this Review, we discuss past and present efforts to overcome the somewhat limited clinical efficacy of PI3Kα pathway inhibitors, including optimization of inhibitor specificity, patient selection and biomarkers across cancer types, with a focus on breast cancer, as well as identification and abrogation of signalling-related and metabolic mechanisms of resistance, and interventions to improve management of prohibitive adverse events. We highlight the advantages and limitations of laboratory-based model systems used to study the PI3K pathway, and propose technologies and experimental inquiries to guide the future clinical deployment of PI3K pathway inhibitors in the treatment of cancer.

Fig. 1 |. The PI3K pathway in non-malignant cells and cancer.

a | Insulin and other growth factors stimulate receptor tyrosine kinases (RTKs), leading to transautophosphorylation at C-terminal domain tyrosine residues. These phosphotyrosines bind to SH2 domains in the regulatory p85α subunit of phosphatidylinositol 3-kinase-α (PI3Kα), activating the enzymatic p110α subunit and thus PI3Kα activity, catalysing the production of phosphatidylinositol 3,4,5-trisphosphate (PIP₃) from phosphatidylinositol 4,5-bisphosphate (PIP₂) in the inner layer of the cell membrane. The lipid phosphatase PTEN can reverse this process. PIP₃ recruits the serine/threonine kinases PDPK1 and AKT to the plasma membrane. Subsequently, PDPK1 and the mTOR complex 2 (mTORC2) phosphorylate AKT at T308 and S473, respectively. AKT then phosphorylates a host of cellular substrates, including tuberin (also known as TSC2), thus inactivating the TSC complex; suppression of the GTPase-activating protein activity of the TSC complex results in the activation of the GTPase RHEB, which in turn activates mTOR complex 1 (mTORC1), which drives numerous necessary processes in normal physiology and cancer. AKT also regulates cellular processes through various targets other than TSC2. b | Structural depiction of the oncogenic activating p110α E545K and H1047R mutations in the crystal structure of PI3Kα (PDB 4OVU). E545K is located at the p110α–p85α binding interface, and H1047R is located in the membrane-binding region. c | In cancer, PI3Kα is often activated through RTK phosphopeptide binding to p85α, p110α mutation or RAS stimulation of p110α. iSH2, inter Src homology 2 domain; niSH2, N-terminal and inter Src homology domains; nSH2, N-terminal Src homology 2 domain.

Fig. 2 |. Drugging the PI3K pathway through the decades.

Timeline summarizing phosphatidylinositol 3-kinase (PI3K) pathway inhibitor drug development. FDA-approved drugs and their indications are boxed. CLL, chronic lymphocytic leukaemia; FL, follicular lymphoma; HR, hormone receptor; MZL, marginal zone lymphoma; NETs, neuroendocrine tumours; PIKK, PI3K-related kinase; RCC, renal cell carcinoma; R/R, relapse and/or refractory; SLL, small lymphocytic lymphoma.

Fig. 3 |. Signalling and epigenetic mechanisms limiting the efficacy of PI3K inhibitors.

a | Classes of signalling resistance mechanisms to phosphatidylinositol 3-kinase (PI3K) inhibitors include (1) PTEN mutation, (2) AKT-independent activation of mTOR complex 1 (mTORC1) signalling by alternative kinases or via loss of negative regulators (such as subunits of the TSC complex), (3) INPP4B amplification leading to phosphatidylinositol 3-phosphate (PI(3)P)-mediated SGK signalling, (4) receptor tyrosine kinase (RTK) amplification or mutation, and (5) mTORC1 activation through crosstalk with other signalling pathways. b | Adaptive resistance mechanism to PI3K inhibitors in oestrogen receptor-positive (ER⁺) breast cancer cells, whereby PI3K inhibition decreases AKT phosphorylation of the histone H3 lysine 4 (H3K4) monomethyltransferase KMT2D, leading to KMT2D activation, H3K4 methylation and an open chromatin state at gene enhancers, and thus to increased ER-dependent transcription. c | Key targets (shown in green) upstream and downstream of PI3K–AKT that, when inhibited, might overcome resistance to PI3K pathway inhibitors. mTORC2, mTOR complex 2; PI(3,4)P₂, phosphatidylinositol 3,4-bisphosphate; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol 3,4,5-trisphosphate; TKIs, tyrosine kinase inhibitors.

Fig. 4 |. Metabolic mechanisms limiting the efficacy of PI3K inhibitors.

a | Phosphatidylinositol 3-kinase (PI3K) inhibitors suppress the activity of not only mutant PI3K in cancer cells but also wild-type (WT) PI3K in non-malignant cells of the liver and other tissues, leading to decreased glucose uptake, hyperglycaemia, and compensatory insulin secretion by the pancreas and thus hyperinsulinaemia. As a result, insulin receptor signalling can restimulate the growth and proliferation of cancer cells, thus attenuating the effects of PI3K inhibitors. b | A ketogenic diet, sodium–glucose co-transporter 2 (SGLT2) inhibitors, mutant-selective PI3K inhibitors and avoidance of maintenance insulin to manage hyperglycaemia are predicted to increase the effective dose, anticancer effects and tolerability of PI3K inhibitors.