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

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Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy

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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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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.CC BY · PubMed Central

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See all 122

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: Sirico, Marianna
D’Angelo, Alberto
Gianni, Caterina
Casadei, Chiara
Merloni, Filippo
De Giorgi, Ugo
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: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
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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