CoChat
Sign Up
Cited by 122PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerAdvanced Breast Cancer Therapies

The DOI matches its Crossref record; 171 of the 174 references it cites were found in a registry or an index.

Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy

Open access
Sirico, Marianna, D’Angelo, Alberto, Gianni, Caterina, Casadei, Chiara, Merloni, Filippo, De Giorgi, Ugo·2023·Cancers
DOI 10.3390/cancers15030703PMC PMC9913212
Open this paper in CoChat — free accountOpen PDF

Abstract

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most commonly mutated pathways in cancer. Consequently, more than 40 compounds targeting key components of this signalling network have been tested in clinical trials among various types of cancer. As the oncogenic activation of the PI3K/AKT/mTOR pathway often occurs alongside mutations in other signalling networks, combination therapy should be considered. In this review, we highlight recent advances in the knowledge of the PI3K pathway and discuss the current state and future challenges of targeting this pathway in clinical practice.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/cancers15030703

Cites

171 of 171 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 The PI3K/AKT/mTOR pathway is involved in tumorigenesis and cancer progression. After being activated by RTKs, GPCR or RAS, PI3K catalyzes the phosphorylation of PIP2 to generate PIP3, which binds and recruits AKT and PDK1. Furthermore, by activating NF-κB and inducing the secretion of MMP, AKT promotes cell invasion while increasing the level of cyclin D1, leading to cell cycle progression. Ultimately, Akt promotes cell growth by phosphorylation of the downstream mTORC1, which activates p70S6K-S6 and inhibits 4E-BP1, resulting in protein synthesis and cell growth. Indeed, mTORC2 activates AKT itself. On the other hand, PTEN exerts its role in modulating the PI3K pathway by suppressing PIP2 to PIP3 conversion. Together with tuberous sclerosis protein 1 (TSC1) and TSC2, PTEN is the main negative regulator of the pathway. Simultaneously, activation of the growth factor receptor tyrosine kinases and G protein-coupled receptors induces RAS/RAF/MEK/ERK signalling, and ERK activation can further contribute to mTORC1 activation.
Figure 1 The PI3K/AKT/mTOR pathway is involved in tumorigenesis and cancer progression. After being activated by RTKs, GPCR or RAS, PI3K catalyzes the phosphorylation of PIP2 to generate PIP3, which binds and recruits AKT and PDK1. Furthermore, by activating NF-κB and inducing the secretion of MMP, AKT promotes cell invasion while increasing the level of cyclin D1, leading to cell cycle progression. Ultimately, Akt promotes cell growth by phosphorylation of the downstream mTORC1, which activates p70S6K-S6 and inhibits 4E-BP1, resulting in protein synthesis and cell growth. Indeed, mTORC2 activates AKT itself. On the other hand, PTEN exerts its role in modulating the PI3K pathway by suppressing PIP2 to PIP3 conversion. Together with tuberous sclerosis protein 1 (TSC1) and TSC2, PTEN is the main negative regulator of the pathway. Simultaneously, activation of the growth factor receptor tyrosine kinases and G protein-coupled receptors induces RAS/RAF/MEK/ERK signalling, and ERK activation can further contribute to mTORC1 activation.CC BY · PubMed Central
Figure 2 Summary of the complex phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signalling pathway and inhibitors.
Figure 2 Summary of the complex phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signalling pathway and inhibitors.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 174 references

Research works printed but not linked: 2

  1. (2022, December 08). Capivasertib Plus Faslodex Reduced the Risk of Disease Progression or Death by 40% versus Faslodex in Advanced HR-Positive Breast Cancer. Available online: https://www.astrazeneca.com/media-centre/press-releases/2022/capivasertib-pfs-in-hr-positive-breast-cancer.html.
  2. (2023, January 01). MTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt—PubMed, Available online: https://pubmed.ncbi.nlm.nih.gov/16452206/.

Cited by

Sorted by citations

Items 101–122 of 122

Related

See all

Metadata

Authors
Sirico, M., D’Angelo, A., Gianni, C., Casadei, C., Merloni, F., & De Giorgi, U.
Affiliations
  • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT)
  • Royal United Hospital (GB)
  • Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
Corresponding author
Sirico, Marianna
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2023-01-23
Volume
15
Issue
3
Pages
703
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers15030703
PMC
PMC9913212
OpenAlex
W4317907174
Cited by
121
References
174
Citations by year
2026: 31 · 2025: 47 · 2024: 33 · 2023: 10
FWCI
3.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, other-oa)
  • AIRUS (submittedVersion)
Funders
Ministero della Salute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
Keywords
PI3K inhibitors, PI3K/AKT/mTOR pathway, cancer therapy, PI3K signaling, Akt, mTOR, combination therapy, clinical trials

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review