PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Antonino Glaviano; Aaron Song Chuan Foo; Hiu Yan Lam; Kenneth Chun-Yong Yap; William Jacot

doi:10.1186/s12943-023-01827-6

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Antonino Glaviano, Aaron Song Chuan Foo, Hiu Yan Lam, Kenneth Chun-Yong Yap, William Jacot, Robert H. Jones, Huiyan Eng, Madhumathy G Nair, Pooyan Makvandi, Birgit Geoerger, Matthew H. Kulke, Richard D. Baird, Jyothi S. Prabhu, Daniela Carbone, Camilla Pecoraro...

BioMed Central (2023) • Volume 22, Issue 1, Pages 138-138

SynthesisNarrativeReviewPDF AvailableGrade Eligible

Overall Assessment

Limited Methodological Quality

Assessment created by PaperScorers Medical AI v0.1.0 on Dec 14, 2025

D+

54/100

Key Takeaways

•PAM pathway is frequently activated in cancer, driving growth, survival and resistance.
•Therapeutics span pan/isoform PI3K, AKT, mTOR (allosteric, ATP-competitive, bi-steric), and PDK1 inhibitors.
•Clinical approvals exist for alpelisib, idelalisib, duvelisib, copanlisib, everolimus, temsirolimus; many others in trials.
•Resistance mechanisms include RTK reactivation, PI3K isoform switching, PTEN loss, MAPK activation, metabolic adaptation.
•Bi-steric mTORC1 inhibitors show promise by strongly engaging 4E-BP1 with fewer feedback liabilities; PAM–ICI combos are under study.

Conclusion

Comprehensive overview; promising avenues include rational combinations, better biomarker-driven selection, and next-gen mTORC1 inhibitors to overcome resistance.

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Quality Dimensions

Bias & Integrity

COI handling, outcome switching, selective reporting

B-72

Methods Rigour

Protocol clarity, sampling, controls

D-34

External Validity

Generalisability, setting, population

C61

Transparency & Reproducibility

Data/code/materials availability, preregistration

D42

Significance & Novelty

Contribution vs prior art; context if known

B-73

Statistical Validity

Models, assumptions, multiplicity, CI priority

F22

Integrity & Transparency

Integrity checks

P-hacking risk?

?

None suspected

Signs of selective hypothesis testing or analysis choices that could inflate false positive rates.

Outcome switching?

?

None suspected

Evidence that primary outcomes were changed during or after the study, potentially distorting results.

Conflict of interest?

?

None suspected

Authors have financial or other relationships that could bias research findings.

Data integrity issues?

?

None suspected

Concerns about the accuracy, completeness, or authenticity of the reported data.

Open science signals

Research data

?

Not applicable

Raw data used in the analyses is publicly available or accessible upon request.

Analysis code

?

Not applicable

Code or scripts used to analyze the data are shared for reproducibility.

Study materials

?

Not applicable

Protocols, questionnaires, and other materials are publicly available.

Premise

Primary Research Question

What are key dysregulations of PAM signalling in cancer and how do targeted therapies perform and fail?

Hypothesis is Falsifiable

—Not specified

Narrative review; no testable hypothesis.

PICO Framework

Population—Not specified

Not an interventional study.

Intervention—Not specified

Multiple drug classes discussed, no single intervention.

Comparison—Not specified

No comparator framework.

Outcome—Not specified

No predefined outcomes.

Literature Positioning

Literature Review Balanced

Well covered

Broad referencing across biology, trials, resistance, and immunology.

Evidence: refs span pp.27–37; Introduction p.2

Research Gap Clearly Stated

Well covered

States aim to highlight dysregulations, therapies, and resistance gaps.

Evidence: p.2 Introduction: 'we highlight… discuss… mechanisms of resistance'

Stated Contribution Clear

Well covered

Defines scope: comprehensive on PAM axis incl. AKT/mTOR and therapies.

Evidence: p.2 Introduction

Study Provenance

Peer reviewed venueGrant funding disclosedNo conflicts declared5 affiliations listed

Authors & Affiliations

Multiple institutions across Singapore, Italy, USA, UK, France and others (header).

Funding Statement

A.P.K. supported by Singapore MOE grant MOE-T2EP30120-0016; other acknowledgements listed.

Conflicts of Interest

Authors declare no competing interests.

Peer Review

✓Published in Molecular Cancer (2023), Open Access; standard peer review.

Evidence: p.27 Declarations; journal header

Methodological Assessment

All design modules are marked as not applicable. Use the accordion below to review their details.

Modules without applicable checklist items (10)

These designs were fully marked as not applicable but remain available for reference.

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Study Overview

Study Design

Narrative Review

Primary classification used to evaluate this research.

Population

Review of PI3K/AKT/mTOR signalling across human cancers and therapies.

Brief summary of who or what was studied.

Pre-registration

Not registered

Indicates whether the protocol or trial was registered before data collection.

Reviewer Notes

Narrative review; descriptive synthesis of pathway biology and clinical trials without systematic methods.

Publication Details

DOI

10.1186/s12943-023-01827-6

Published

August 18, 2023

Citations

1396 citations

FWCI

259.57

External Resources

DOI Link OpenAlex

Disclaimer: This assessment is generated by AI and should not be the sole basis for clinical or research decisions. Always review the original paper and consult with domain experts.

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