PI3K/AKT/mTOR Axis in Cancer: From Pathogenesis to Treatment

Abstract

The PI3K/AKT/mTOR signaling axis is a pivotal regulator of key cellular functions, including proliferation, metabolism, survival, and immune modulation. In cancer, its dysregulation drives malignant transformation, tumor progression, therapeutic resistance, and immune evasion. Despite numerous studies, an integrated understanding of this pathway's multifaceted role in tumor biology and treatment remains incomplete. This review comprehensively outlines the oncogenic mechanisms governed by the PI3K/AKT/mTOR pathway, including its regulation of epithelial-mesenchymal transition, autophagy, apoptosis, glycolysis, ferroptosis, and lipid metabolism. We emphasize the dual role of autophagy, its interplay with therapeutic resistance, and its contextual impact on cancer dynamics. Moreover, we explore the epigenetic regulation of this axis by noncoding RNAs (miRNAs, lncRNAs, circRNAs) and its influence on tumor hallmarks. The review also highlights the pathway's involvement in modulating responses to chemotherapy, radiotherapy, and immunotherapy, as well as its role in remodeling the tumor microenvironment. We critically evaluate emerging therapeutic strategies targeting the PI3K/AKT/mTOR axis, including small-molecule inhibitors, phytochemicals, and nanoparticle-based systems. By elucidating the integrated landscape of this pathway, our review highlights its value as a central therapeutic target and offers insights into precision oncology approaches aimed at overcoming drug resistance and enhancing treatment efficacy.

Keywords: PI3K/AKT/mTOR axis; cancer therapy; chemotherapy and immunotherapy; drug delivery; molecular pathway.

FIGURE 1

A schematic representation of PI3K/AKT/mTOR axis (adapted with permission from Ref. [25]). Two receptors including RTKs and GPCRs exert a significant function in the induction of PI3K. GPCRs can interact with p85 and p110 subunits of PI3K to elevate the generation of PIP3. A similar strategy is followed by RTKs interacting with IRS and PI3K to trigger PIP3 generation. PTEN is a negative regulator through suppressing PIP2 conversion to PIP3. The generated PIP3 stimulates PDK1 and mTORC2 to enhance levels of AKT. On the other hand, activated AKT enhances the levels of MDM2 and NF‐kB, while it downregulates FOXO, GSK3, Bad and TSC1/2. The stimulation of PI3K/AKT/mTOR axis has been demonstrated in the various cancers [26, 27, 28]. AKT, protein kinase B; BAD, Bcl‐2‐associated death promoter; FOXO, Forkhead box O; GPCRs, G protein‐coupled receptors; GSK3, glycogen synthase kinase 3; IRS, insulin receptor substrate; KRAS, Kirsten rat sarcoma viral oncogene homolog; MAPK/ERK, mitogen‐activated protein kinase/extracellular signal‐regulated kinase; MDM2, mouse double minute 2 homolog; MEK, mitogen‐activated protein kinase kinase; mTORC1/2, mechanistic target of rapamycin complex 1/2; NF‐κB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; PDK1, 3‐phosphoinositide‐dependent protein kinase‐1; PI3K, phosphoinositide 3‐kinase; PIP2, phosphatidylinositol 4,5‐bisphosphate; PIP3, phosphatidylinositol 3,4,5‐trisphosphate; PTEN, phosphatase and tensin homolog; Raf, rapidly accelerated fibrosarcoma kinase; Rheb, Ras homolog enriched in brain; RTKs, Receptor tyrosine kinases; TSC1/2, tuberous sclerosis complex 1 and 2; (created with Biorender.com).

FIGURE 2

Mutations in the PI3K‐related genes (adapted with permission from Ref. [29]). PIK3CA, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha; PIK3CB, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit beta; PIK3R1, phosphoinositide‐3‐kinase regulatory subunit 1; PTEN, phosphatase and tensin homolog; (created with Biorender.com).

FIGURE 3

The regulation of PI3K/AKT/mTOR at the RNA and DNA levels. In response to growth factors or cytokines, receptor tyrosine kinases (RTKs) are activated and attract PI3K to the plasma membrane. At the membrane, PI3K catalyzes the conversion of PI(4,5)P2 to PI(3,4,5)P3, which then activates AKT via PDK1 and mTORC2. Activated AKT promotes several cellular functions, such as cell cycle progression, proliferation, apoptosis suppression, glucose metabolism, cell survival, actin cytoskeleton structure, transcription, motility, and movement. It accomplishes this by phosphorylating downstream targets like TSC2, so alleviating TSC2‐induced inhibition of Rheb and facilitating mTORC1 activation at the lysosome. Moreover, mTORC1 activity is modulated by amino acids through distinct sensors such as regulator, V‐ATPase, and notably Rags, which position mTORC1 at the lysosome. Upon activation, mTORC1 stimulates protein synthesis, increases nucleotide production, and suppresses autophagy and proteasomal degradation (adapted with permission from Ref. [30]). 4E‐BP1, eukaryotic translation initiation factor 4E‐binding protein 1; AKT, protein kinase B; ATG13, autophagy related 13; CAD, carbamoyl‐phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; CLIP‐170, cytoplasmic linker protein of 170 kDa; CREB, cAMP response element‐binding protein; Deptor, DEP domain containing MTOR‐interacting protein; FLCN/FNIP2, folliculin/folliculin interacting protein 2; FOXO, Forkhead Box O; GRB10, growth factor receptor‐bound protein 10; GSK3, glycogen synthase kinase 3; HIF‐1α, hypoxia‐inducible factor 1‐alpha; IGF‐1R, insulin‐like growth factor 1 receptor; InsR, insulin receptor; KISTOR, Kidney‐specific TOR‐interacting protein; MDM2, mouse double minute 2 homolog; mLST8, mammalian lethal with SEC13 protein 8; mTORC1, mechanistic target of rapamycin complex 1; mTORC2, mechanistic target of rapamycin complex 2; NF‐κB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; PDK1, 3‐phosphoinositide‐dependent protein kinase‐1; PI3K, phosphoinositide 3‐kinase; PIP2, phosphatidylinositol 4,5‐bisphosphate; PIP3, phosphatidylinositol 3,4,5‐trisphosphate; PKCα, protein kinase C alpha; Pras40, proline‐rich AKT substrate of 40 kDa; PTEN, phosphatase and tensin homolog; RagA/B/C/D, Ras‐related GTP‐binding proteins; Raptor, regulatory associated protein of mTOR; Rheb, Ras homolog enriched in brain; Rictor, rapamycin‐insensitive companion of mTOR; RTKs, receptor tyrosine kinases; S6K, ribosomal protein S6 kinase; SGK1, serum and glucocorticoid regulated kinase 1; SLC38A9, solute carrier family 38 member 9; TSC1/2, tuberous sclerosis complex 1 and 2; ULK1, Unc‐51 like autophagy activating kinase 1; V‐ATPase, vacuolar‐type H+‐ATPase; WEE1, WEE1 G2 checkpoint kinase; (created with Biorender.com).

FIGURE 4

The function of PI3K/AKT in the modulation of autophagy and EMT. Several kinds of therapeutic compounds have been introduced to regulate PI3K/AKT/mTOR axis in affecting EMT and autophagy in human cancers including quinacrine, ceiranib, curcumin, cucurbitacin B, thymoquinone, PtoxDpt, and cisplatin. The problem is related to the dual function of autophagy in cancer providing some challenges regarding induction or inhibition of PI3K/AKT/mTOR axis to modulate it. PI3K/AKT/mTOR axis has been able to regulate EMT in the different cancers including gastric cancer, bladder tumor, and pancreatic cancer, among others; (created with Biorender.com).

FIGURE 5

The regulation of apoptosis and ferroptosis by PI3K/AKT/mTOR. Upregulation of this pathways reduces apoptosis and ferroptosis causing chemoresitance, while its inhibition enhances cell death. A number of therapeutics including curcumin, auriculasin, bupivacaine, and cryptotanshinone can downregulate PI3K/AKT to stimulate apoptosis and ferroptosis; (created with Biorender.com).

FIGURE 6

(A) There are different kinds of ncRNAs with both oncogenic and onco‐suppressor functions regulating PI3K/AKT/mTOR axis. The miRNAs can be sponged by circRNAs and lncRNAs to further affect PI3K/AKT expression. These interactions can finally regulate cancer hallmarks including proliferation, metastasis, and drug resistance. (B) The involvement of PI3K/AKT in the drug resistance and radioresistance. It can regulate glycolysis, apoptosis, and immune evasion in chemoresistance with therapeutics such as salvigenin and others capable of downregulating PI3K/AKT. In radioresistance, PI3K/AKT regulates autophagy, DNA repair, and apoptoss in which CAL101 and LY294002 can suppress PI3K/AKT in enhancing response to radiotherapy; (created with Biorender.com).