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Updated: Oct 4, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer
Xueliang Gao1,2,3, Yubao Wang1,2, Caroline F Ribeiro4,5
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110β dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110β inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110β/RAC/PAK1 and β-catenin pathways in CRPC, we found that combining p110β with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110β activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC.
Implications:
This work establishes p110β as a promising target for preventing the progression of primary PTEN-deficient prostate tumors to CRPC, and for treating established CRPC in combination with RAC/PAK1 or tankyrase inhibitors.
Insights
Targeting PI3K-beta (p110β) shows promise in slowing prostate cancer progression to castration-resistant prostate cancer (CRPC). Combination therapies targeting p110β with RAC/PAK1 or tankyrase inhibitors offer new treatment strategies for CRPC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Androgen deprivation therapy for prostate cancer often leads to disease relapse and castration-resistant prostate cancer (CRPC).
- Genomic alterations, particularly PI3K hyperactivation, are implicated in CRPC development.
- PTEN-deficient models are crucial for studying CRPC progression.
Purpose of the Study:
- To investigate the role of PI3K p110 catalytic isoforms in a murine model of PTEN-null invasive CRPC.
- To identify novel therapeutic targets for preventing CRPC progression and treating established CRPC.
Main Methods:
- Utilized a murine model of PTEN-null invasive CRPC.
- Examined the effects of genetic and pharmacologic inhibition of PI3K p110α and p110β.
- Conducted genomic analyses to identify key pathways involved in CRPC.
- Tested combination therapies in murine and human CRPC organoids in vitro and in vivo.
Main Results:
- Inhibition of PI3K p110α had minimal impact on CRPC development.
- Perturbation of PI3K p110β significantly slowed CRPC initiation and progression.
- Established CRPC tumors developed partial resistance to p110β inhibition.
- Combined p110β inhibition with RAC/PAK1 or tankyrase inhibitors reduced CRPC growth.
Conclusions:
- PI3K p110β is a critical target for preventing prostate tumor progression to CRPC.
- Targeting p110β in combination with RAC/PAK1 or tankyrase inhibitors represents a viable therapeutic strategy for CRPC.
- PI3K p110β inhibition offers a promising approach with minimal impact on physiological processes.
