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INTERNATIONAL CONGRESS OF

PharmacoGenetics

• Epigenetic Regulation of the PI3K/AKT/mTOR Pathway in Cancer: A Systematic Review of Mechanisms and Therapeutic Implications

• Maryam Radmanfard,^1,* Asal Naghipour_Kordlar,²
  1. Department of Basic Sciences, Ta.C., Islamic Azad University, Tabriz, Iran
  2. Faculty of Nursing, Tabriz University of Medical Sciences, Tabriz, Iran
  
  
  
• Introduction: The PI3K/AKT/mTOR signaling pathway is one of the most frequently altered cascades in human cancers. Its dysregulation promotes hallmark oncogenic processes such as uncontrolled proliferation, metabolic rewiring, angiogenesis, metastasis, and resistance to chemotherapy, targeted therapy, and immunotherapy. While genomic alterations (e.g., PIK3CA mutations, PTEN loss, AKT1 amplification, and mTOR mutations) explain part of the deregulation, epigenetic mechanisms heritable but reversible changes in gene expression are increasingly recognized as key regulators {Yang, 2019 #67}. Epigenetic regulation encompasses DNA methylation, histone post-translational modifications, and non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). These processes not only control expression of PI3K/AKT/mTOR pathway components but are themselves modulated by signaling output, creating feedback loops that reinforce oncogenic signaling {Yu, 2021 #72}. Given the growing therapeutic interest in epigenetic drugs (e.g., DNMT inhibitors, HDAC inhibitors, EZH2 inhibitors), it is critical to systematically evaluate how epigenetic regulation contributes to PI3K/AKT/mTOR signaling in cancer. This review addresses {Martini, 2014 #69}: 1. Epigenetic mechanisms regulating pathway activity. 2. Reciprocal effects of pathway activation on the cancer epigenome. 3. Therapeutic opportunities from co-targeting epigenetic regulators and PI3K/AKT/mTOR signaling.
• Methods: A systematic search was performed in PubMed, Scopus, and Web of Science databases up to June 2025 using the terms: PI3K, AKT, mTOR, epigenetics, DNA methylation, histone modification, ncRNA, cancer. • Inclusion criteria: Original research studies (in vitro, in vivo, clinical). Studies reporting mechanistic insights into epigenetic regulation of PI3K/AKT/mTOR. Preclinical or clinical data on therapeutic targeting of these interactions. • Exclusion criteria: Non-cancer studies. Reviews (used only as background). Reports lacking mechanistic relevance. From 512 records, 148 full texts were reviewed, and 74 studies were included.
• Results: 1. DNA Methylation DNA methylation at CpG islands within promoter regions is a frequent epigenetic mechanism silencing tumor suppressors: • PTEN silencing through promoter hypermethylation was consistently observed in breast, prostate, endometrial, and glioblastoma models. Loss of PTEN results in unchecked PI3K/AKT activation. • INPP4B and PIK3IP1, other negative regulators, also exhibited promoter hypermethylation. • Mechanistically, AKT phosphorylates DNMT1, increasing its stability and perpetuating abnormal methylation, creating a self-reinforcing cycle {Mohite, 2023 #62}. 2. Histone Modifications Histone acetylation and methylation patterns critically modulate chromatin accessibility for PI3K/AKT/mTOR-related genes. • EZH2, a histone methyltransferase, was found to be directly phosphorylated by AKT, enhancing its methyltransferase activity and silencing tumor suppressor genes. • Overexpression of HDACs correlated with enhanced signaling. Preclinical studies demonstrated that HDAC inhibitors (e.g., vorinostat, panobinostat) resensitize tumors to PI3K/mTOR inhibitors. • p300/CBP acetyltransferases were shown to regulate transcription of PI3K subunits and downstream growth factors, reinforcing pathway signaling {Ersahin, 2015 #73}. 3. Non-Coding RNAs a) MicroRNAs (miRNAs) • Tumor-suppressive miRNAs such as miR-126, miR-34a, and miR-143 directly inhibit PI3K subunits or AKT. • Oncogenic miRNAs including miR-21, miR-221/222 suppress PTEN expression, promoting sustained AKT activity. b) Long Non-Coding RNAs (lncRNAs) • HOTAIR, MALAT1, and UCA1 enhance pathway activation by recruiting chromatin modifiers to silence PTEN or by sponging tumor-suppressive miRNAs. c) Circular RNAs (circRNAs) • circRNAs act as “miRNA sponges” to relieve suppression of PI3K/AKT/mTOR. For example, circHIPK3 sequesters miR-124, leading to enhanced AKT activation {Mohite, 2023 #62}. 4. Epitranscriptomics (m6A RNA Methylation) Emerging studies implicate N6-methyladenosine (m6A) modifications in regulating transcript stability and translation efficiency of PI3K/AKT/mTOR pathway components {Owusu-Brackett, 2019 #66}. • m6A writers (METTL3/14) and erasers (FTO, ALKBH5) indirectly shape pathway activation. • Elevated METTL3 expression was linked to increased AKT phosphorylation in leukemia and glioblastoma. 5. Reciprocal Regulation PI3K/AKT/mTOR signaling remodels the epigenome: • AKT phosphorylates and activates EZH2 and DNMT1. • mTORC1 influences acetyl-CoA availability, indirectly modulating histone acetylation. • p300/CBP and HDACs are transcriptionally regulated downstream of mTOR signaling. This creates feedback loops, reinforcing tumor heterogeneity and therapy resistance {Sheppard, 2012 #71}. Discussion The reviewed evidence underscores the bidirectional interplay between epigenetic mechanisms and PI3K/AKT/mTOR signaling. These findings reveal multiple vulnerabilities: • Epigenetic silencing of tumor suppressors (PTEN, INPP4B). • Oncogenic activation through ncRNAs and histone methyltransferases. • Positive feedback loops sustaining tumor progression. Importantly, tumors with similar genetic mutations can exhibit heterogeneous phenotypes due to epigenetic variability, explaining inconsistent therapeutic responses. Therapeutic Implications 1. Combination Strategies Preclinical studies show synergy between PI3K/mTOR inhibitors and epigenetic drugs (HDAC inhibitors, EZH2 inhibitors, DNMT inhibitors) {Sheppard, 2012 #71}. o Dual targeting reduces adaptive resistance and induces stronger apoptosis {Owusu-Brackett, 2019 #66}. 2. Biomarker Development o DNA methylation status of PTEN and expression signatures of ncRNAs can stratify patients for PI3K/AKT/mTOR inhibitor therapy. o Liquid biopsy approaches measuring circulating ncRNAs provide non-invasive monitoring tools {Asati, 2016 #74}. 3. Precision Oncology o Integrating multi-omics (genomics, epigenomics, transcriptomics, proteomics) is essential for capturing the complexity of PI3K/AKT/mTOR regulation. o AI-driven biomarker discovery offers powerful predictive modeling for therapeutic response {Lim, 2015 #65}. Future Directions • Epigenome Editing: CRISPR/dCas9-based tools enable locus-specific editing of DNA methylation or histone modifications, offering targeted restoration of tumor suppressors. • Single-cell Multi-omics: Resolving intratumoral heterogeneity will guide personalized combination therapies. • Epitranscriptomic Therapeutics: Targeting m6A regulators holds promise for future interventions. • Clinical Trials: More phase I/II studies are needed to validate combined PI3K/epigenetic inhibition strategies {Janku, 2018 #64}.
• Conclusion: Epigenetic regulation of the PI3K/AKT/mTOR pathway is a central mechanism in cancer progression. DNA methylation, histone modifications, and non-coding RNAs dynamically control signaling activity while being reciprocally shaped by pathway output. This self-reinforcing loop underlies therapy resistance and tumor heterogeneity. Rational combination therapies, guided by validated epigenetic biomarkers, represent the most promising strategy for clinical translation. Integration of multi-omics and advanced technologies will be essential for advancing precision medicine targeting this pathway.
• Keywords: PI3K/AKT/mTOR pathway, Epigenetics, Cancer, DNA methylation, Histone modification