Related Experiment Video
Updated: Nov 27, 2025
An Orthotopic Murine Model of Human Prostate Cancer Metastasis
Published on: September 18, 2013
Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of
Andreea D Stuparu1, Joseph R Capri2, Catherine A L Meyer3
1Atreca Inc., South San Francisco, California.
Abstract:
Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is effective against prostate cancer (PCa), but all patients relapse eventually. Poor understanding of the underlying resistance mechanisms represents a key barrier to development of more effective RLT. We investigate the proteome and phosphoproteome in a mouse model of PCa to identify signaling adaptations triggered by PSMA RLT. Methods: Therapeutic efficacy of PSMA RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53 tumor-bearing nonobese diabetic scid γ-mice. Two days after RLT, the proteome and phosphoproteome were analyzed by mass spectrometry. Results: PSMA RLT significantly improved disease control in a dose-dependent manner. Proteome and phosphoproteome datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, phosphatidylinositol-3-kinase/AKT, and MYC signaling. C4-2 TP53 tumors were less sensitive to PSMA RLT than were parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusion: We identified signaling alterations that may mediate resistance to PSMA RLT in a PCa mouse model. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients.
Insights
Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) shows promise for prostate cancer (PCa), but resistance emerges. This study identified key signaling pathways involved in PSMA RLT resistance in a PCa mouse model.
Area of Science:
- Oncology
- Molecular Biology
- Proteomics
Background:
- Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is a promising treatment for prostate cancer (PCa).
- Therapeutic resistance limits the long-term efficacy of PSMA RLT, necessitating a deeper understanding of resistance mechanisms.
- Identifying signaling adaptations post-PSMA RLT is crucial for developing more effective combination therapies.
Purpose of the Study:
- To investigate the proteome and phosphoproteome changes in a PCa mouse model following PSMA RLT.
- To identify signaling pathways activated by PSMA RLT that may contribute to treatment resistance.
- To explore the role of TP53 in mediating responsiveness to PSMA RLT.
Main Methods:
- Therapeutic efficacy of PSMA RLT was evaluated using tumor volume, time to progression, and survival in mouse models.
- Proteomic and phosphoproteomic analyses were performed using mass spectrometry on tumor samples after RLT.
- Comparison of PSMA RLT sensitivity between C4-2 and C4-2 TP53 knockout tumors was conducted.
Main Results:
- PSMA RLT demonstrated dose-dependent improvement in disease control in the PCa mouse model.
- Proteomic and phosphoproteomic analyses revealed activation of genotoxic stress response pathways, including DNA damage/replication stress, TP53, androgen receptor, PI3K/AKT, and MYC signaling.
- TP53-deficient tumors exhibited reduced sensitivity to PSMA RLT, indicating a role for TP53 in treatment response.
Conclusions:
- Signaling alterations mediating resistance to PSMA RLT were identified in a preclinical PCa model.
- The findings highlight the involvement of genotoxic stress, TP53, androgen receptor, PI3K/AKT, and MYC pathways in PSMA RLT resistance.
- This research provides a foundation for developing rational combination therapies to overcome PSMA RLT resistance and improve patient outcomes in PCa.
