PI3Kδ as a Novel Therapeutic Target for Aggressive Prostate Cancer
1
Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA
2
Hormone Related Cancers Program, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(10), 1610; https://doi.org/10.3390/cancers17101610
Submission received: 23 March 2025
/
Revised: 30 April 2025
/
Accepted: 8 May 2025
/
Published: 9 May 2025
(This article belongs to the Special Issue New Insights into Urologic Oncology)
Simple Summary
Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths among men in the United States. PI3K/AKT/mTOR signaling is frequently upregulated in prostate cancer. Therefore, targeting PI3K or PI3K/AKT/mTOR signaling pathway is considered a promising therapeutic option for treating prostate cancers. In this review article, we comprehensively discuss the oncogenic roles of PI3Kδ (one of the class IA PI3Ks) in the development and progression of prostate cancer. We further summarize the recent progress and future direction on the development of the PI3Kδ-based precision biomarkers and therapeutics for prostate cancer diseases in preclinical models and clinical trials.
Abstract
Phosphoinositide 3-kinases (PI3Ks) signaling represents an important pathway regulating cell proliferation, survival, invasion, migration, and metabolism. Notably, PI3K/AKT/mTOR signaling is frequently dysregulated in the majority of malignancies. Among the class IA PI3Ks (PI3Kα/β/δ), emerging evidence has implicated that PI3Kδ is not only overexpressed in leukocytes but also in solid tumors, including prostate cancer. The critical role of PI3Kδ in tumorigenesis and in the creation of a suppressive tumor microenvironment, along with the recent finding of PI3Kδ splice isoforms in promoting tumor aggressiveness and resistance, further demonstrates the potential of developing novel PI3Kδ-targeted cancer therapies. In this review, we comprehensively describe the functional mechanisms underlying the PI3Kδ-driven tumor progression and immune regulation in prostate cancer diseases. Furthermore, the recent preclinical and clinical studies on the development of PI3Kδ-/PI3K-targeted inhibitors as single agents and in combination therapies (with chemotherapy, radiation, hormone therapy, or immunotherapy) are summarized. Finally, we discuss the potential novel therapies for improving the treatment efficacies, as well as the current limitations and challenges of PI3Kδ-based therapies for prostate cancer.
