Open research questions in PI3K/AKT/mTOR signaling in cancer

What the literature leaves open

• Although eIF5A shuttles between the nucleus and cytoplasm, its specific nuclear roles remain poorly defined.

  eIF5A coordinates the transcription and translation of its target genes · 2026 · DOI

• Chronic elevation of AngII contributes to cardiac pathology, but the mechanisms linking sustained AngII signaling to heart dysfunction remain incompletely understood.

  Phosphoinositide Depletion and Compensatory Phospho-Signaling in Angiotensin II-Induced Heart Disease · 2026 · DOI

• Abstract Background Although inhibitors of mRNA translation are being evaluated as anti-cancer agents, the dynamics of protein synthesis throughout tumour progression are still poorly understood.

  Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer · 2026 · DOI

• Whether glutaminolytic transcription scales with PTEN copy-number loss in human tumors, and by what mechanism, has not been established.

  Passenger co-deletion confounds glutaminolysis signatures anchored on PTEN loss: a cautionary case for location-aware signature design · 2026 · DOI

• Despite extensive research into the genotype-phenotype correlations of PTEN mutations, the mechanisms underlying the dual association of specific PTEN mutations with both cancer and ASD (PTEN-cancer/ASD mutations) remain elusive.

  Machine Learning and Structural Dynamics-Based Approach to Reveal Molecular Mechanism of PTEN Missense Mutations Shared by Cancer and Autism Spectrum Disorder · 2025 · DOI

• As a peripheral membrane protein, PI3Kα is activated at the membrane, however, its active conformation remains unknown.

  Structural and allosteric effects of the membrane-bound PI3Kα H1047R mutation and opportunities for drug discovery · 2025 · DOI

• LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear.

  LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models · 2025 · DOI

• However, an understanding of the role of lysolipid transport and salvage in regulating cellular lipid homeostasis and in disease is lacking.

  SPNS1 variants cause multiorgan disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis · 2025 · DOI

• However, clinical success for PI3K inhibitors (PI3Kis) has been limited by their narrow therapeutic window.

  USP10/GSK3β-mediated inhibition of PTEN drives resistance to PI3K inhibitors in breast cancer · 2025 · DOI

• The underlying genetic abnormalities that cause the phenotypic variation seen in patients with PTEN hamartoma tumor syndrome (PHTS) are poorly understood.

  Lessons from the Oncology Clinic: Repurposing PI3K Pathway Inhibitors for the Treatment of PTEN Hamartoma Tumor Syndrome · 2025 · DOI

• Mammalian target of rapamycin (mTOR) can regulate the differentiation of T cells, but the specific pathway leading mTOR to regulate Th17/Treg cells in UC remains unclear.

  mTOR promotes an inflammatory response through the HIF1 signaling pathway in ulcerative colitis · 2024 · DOI

• However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood.

  TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC–induced murine hepatocarcinogenesis via centromere protein M · 2024 · DOI

• The lack of effective therapies for renal cell carcinoma. The need for a better understanding of the PI3K-AKT-mTOR signaling pathway's role in the disease.

  The mechanism of the PI3K-AKT-mTOR signaling pathway in renal cell carcinoma: current developments and future prospects · 2026 · DOI

• Can Zou 1, Yuxia Wang 2, Qiuyan Chen 1, Jianyou Shi 3*, Xianbo Wu 1* and Quan Luo 4* 1School of Sports Medicine and Health, Chengdu Sport University, Chengdu, Sichuan, China, 2Department of Pharmacy, Sichuan Academy of Medical Sciences&Sichuan Provincial People’s Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China, 3Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China, 4West China School of Medicine, Sichuan University, The Second People’s Hospital of Chengdu Affiliated to Sichuan University, Chengdu Second People’s Hospital, Chengdu, Sichuan, China Renal cell carcinoma (RCC) is a type of solid tumor with one of the highest incidences among urinary system malignancies, and its incidence continues to increase worldwide. The PI3K-AKT-mTOR signaling pathway, as a central signaling hub that regulates biological processes such as cell survival, proliferation, metabolism, and metastasis, often exhibits abnormal and sustained activation during the pathological progression of RCC. Dysregulation of this pathway synergistically promotes tumor progression through multiple mechanisms, including enhancing the survival and clonal expansion of tumor cells, inducing angiogenesis, driving metabolic reprogramming of the tumor microenvironment, and mediating treatment resistance. These pathological changes are closely associated with poor patient prognosis. Given the central role of the PI3K-AKT-mTOR signaling pathway in the pathogenesis of RCC, it has become a key target for targeted therapeutic intervention. Although multiple small-molecule inhibitors targeting this pathway have demonstrated potential for inhibiting tumor growth in preclinical studies and early-phase clinical trials, their clinical application still faces numerous challenges. Against this backdrop, combination therapy strategies offer a new approach to overcome the limitations of single-agent therapy, not only enhancing treatment efficacy but also potentially reducing the risk of drug resistance. Notably, natural products and their derivatives, due to their low toxicity, ability to modulate multiple targets, and specific inhibitory effects on cancer stem cells, are regarded as promising sensitizers in combination therapy.

  The mechanism of the PI3K-AKT-mTOR signaling pathway in renal cell carcinoma: current developments and future prospects · 2026 · DOI

• Investigating the role of AKT inhibition in overcoming endocrine resistance, - Exploring combination strategies with other therapeutic agents, - Further studies on biomarker-selected populations and emerging resistance mechanisms

  Capivasertib as a Therapeutic Agent for Breast Cancer: Targeting AKT to Overcome Endocrine Resistance · 2026 · DOI

• The majority of patients with HR+/HER2- breast cancer develop endocrine resistance, resulting in disease progression. There is a need for therapeutic agents that can overcome or delay endocrine resistance. The PI3K/AKT/mTOR signaling cascade represents a critical indication of endocrine resistance and tumor progression in HR+/HER2- breast cancer.

  Capivasertib as a Therapeutic Agent for Breast Cancer: Targeting AKT to Overcome Endocrine Resistance · 2026 · DOI

• Notably, during the revision pro- cess of our study, intrabodies targeting the FKBP12–rapamycin-binding site of mTOR were reported, although their specificity is of concern as the intrabodies showed inhibition to both mTORC1 and mTORC2 and the off-target effects of the intrabodies have not been evaluated72.

  Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1 · 2026 · DOI

• Together with RMC-6236’s broad MHC-I upregulation across variants, these findings indicate that KRASG12R-expressing tumors may possess distinct immunogenicity, warranting further investigation into mutation-specific immune regulation and subtype-tailored immunotherapy strategies.

  PDAC Models with KRASG12R Show Elevated MHC Class I Expression · 2026

• The rarity of mammary MCA makes it challenging to study. The limited molecular characterization of mammary MCA hinders diagnosis and treatment.

  Molecular characterization of mammary mucinous cystadenocarcinoma reveals recurrent TP53 and RB1 alterations with frequent PI3K–AKT pathway abnormalities · 2026 · DOI

• There is limited molecular characterization of mammary MCA. The genetic alterations and tumor mutation burden of mammary MCA are not well understood.

  Molecular characterization of mammary mucinous cystadenocarcinoma reveals recurrent TP53 and RB1 alterations with frequent PI3K–AKT pathway abnormalities · 2026 · DOI

• The limited understanding of the role of PGAM5 in AML. The need for novel therapeutic targets for AML.

  Unveiling the novel role of PGAM5 in rewiring metabolism through PI3K/AKT/mTOR signaling in acute myelogenous leukemia · 2026 · DOI

• Further investigation of Pinoresinol's anti-cancer effects in vivo. Analysis of Pinoresinol's interaction with other signaling pathways. Development of new anti-cancer therapies targeting PI3Kα.

  Pinoresinol Induces Apoptosis and Cell-Cycle Arrest and Suppresses PI3K/Akt/mTOR Signaling in Lung Cancer Cells: An In Vitro and In Silico Study · 2026 · DOI

• The need for new anti-cancer therapies with improved efficacy and reduced side effects. The limited understanding of the molecular mechanisms underlying anti-cancer agents.

  Pinoresinol Induces Apoptosis and Cell-Cycle Arrest and Suppresses PI3K/Akt/mTOR Signaling in Lung Cancer Cells: An In Vitro and In Silico Study · 2026 · DOI

• ALKBH2 safeguards genomic integrity by reversing alkylation damage, yet its potential role beyond repair—specifically in modulating the Warburg effect—remains unexplored in bladder cancer.

  ALKBH2 promotes the Warburg effect and bladder cancer progression under hypoxic conditions via the PI3K/AKT pathway · 2026 · DOI

• The need for a comprehensive understanding of how protein kinase inhibitors regulate ABC transporters. The lack of a thorough evaluation of the effect of protein kinase inhibitors on ABC transporters through various mechanisms.

  Protein Kinase Inhibitors as Regulators of ABC Transporters in Overcoming Cancer Multidrug Resistance: A Comprehensive Review of Recent Advances · 2026 · DOI

Most-cited papers in PI3K/AKT/mTOR signaling in cancer

• The role of protein kinase C in cell surface signal transduction and tumour promotion · Nature · 1984 · 5,721 citations
• Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex · Science · 2005 · 5,617 citations
• The Phosphoinositide 3-Kinase Pathway · Science · 2002 · 4,602 citations
• Mammalian MAP kinase signalling cascades · Nature · 2001 · 4,286 citations
• Oncogenic kinase signalling · Nature · 2001 · 3,054 citations
• An inhibitor of Bcl-2 family proteins induces regression of solid tumours · Nature · 2005 · 2,979 citations
• A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 · Nature · 1993 · 2,763 citations
• p21 is a universal inhibitor of cyclin kinases · Nature · 1993 · 2,582 citations
• PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? · Frontiers in Oncology · 2022 · 555 citations
• mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging · Annals of the New York Academy of Sciences · 2015 · 201 citations

Most recent work

• Structure of the lysosomal KICSTOR-GATOR1-SAMTOR nutrient-sensing supercomplex · Cell · 2026
• The role and significance of the PI3K/Akt-mTOR signaling pathway in infectious diseases · Frontiers in Cellular and Infection Microbiology · 2026
• Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets · Communications Chemistry · 2026
• Nitric Oxide-Mediated S-Nitrosylation of TSC2 Drives mTOR dysregulation across Shank3 and Cntnap2 Models of Autism Spectrum Disorder · Molecular Psychiatry · 2026
• Aberrant amino acid-sensing promotes immunotherapy resistance via the inflammatory cytokine–ZBTB5–mTORC1 axis · Nature Cell Biology · 2026
• Spatial dynamics of mTOR pathway activity during bovine embryo development · Frontiers in Cell and Developmental Biology · 2026
• Phosphoinositide Depletion and Compensatory Phospho-Signaling in Angiotensin II-Induced Heart Disease · Circulation Research · 2026
• Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1 · Nature Chemical Biology · 2026
• The novel curcumin analogue AKT-100 targets both mutant p53 and STAT3 in gynecologic cancer cells · bioRxiv · 2026
• SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation · Journal of Clinical Investigation · 2026

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