Targeting the PI3K/Akt Signaling Pathway: A Promising Therapeutic Strategy to Reduce Cancer Mortality and Overcome Chemoresistance
Md MohiuddinABSTRACT
Background and Aims
The phosphatidylinositol 3‐kinase (PI3K)/Akt signaling pathway is a central regulator of cellular properties that are essential for cancer progression, including cellular growth, survival, metabolism, and angiogenesis. Dysregulated PI3K/Akt signaling, often caused by genetic alterations in PIK3CA, loss of PTEN, or the overexpression of receptor tyrosine kinases, drives tumor growth and metastasis, as well as immune escape and, crucially, chemoresistance.
Methods
Relevant information was extracted from published articles available in PubMed, Scopus, and Google Scholar. The keywords “PI3K,” “Akt,” “mTOR,” and “chemoresistance” were used to search for relevant information. Overall survival (OS) was analyzed using the Kaplan–Meier method.
Results
Pharmacological targeting of the PI3K/Akt signaling axis represents a promising therapeutic strategy to overcome therapeutic resistance and reduce cancer mortality. The overexpression of AKT1 and PIK3CA was associated with worse patient survival in BRCA, DLBC, KICH, LIHC, and UCEC cancers. This review summarizes the oncogenic roles of PI3K/Akt signaling, the mechanisms underlying chemoresistance, and the therapeutic potential of PI3K/Akt inhibitors as monotherapy or in combination with other agents. In addition, we discuss pathway crosstalk, compensatory signaling activation, metabolic rewiring, tumor microenvironment remodeling, immune evasion, and emerging resistance mechanisms that limit durable clinical responses. We further provide a critical overview of current clinical limitations, including toxicity, adaptive resistance, biomarker challenges, and translational barriers associated with PI3K/Akt‐targeted therapies.
Conclusion
A comprehensive mechanistic understanding of PI3K/Akt signaling and its adaptive resistance networks is essential for optimizing precision therapeutic strategies and improving the long‐term clinical efficacy of PI3K/Akt‐targeted therapies.