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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
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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.

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Crossref · 10.3390/cancers15030703

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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

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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/.

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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

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