Andreea D Stuparu1, Joseph R Capri2, Catherine A L Meyer3, Thuc M Le3, Susan L Evans-Axelsson4, Kyle Current3, Mark Lennox5, Christine E Mona3,6,7, Wolfgang P Fendler8, Jeremie Calais3,6,7, Matthias Eiber9, Magnus Dahlbom3, Johannes Czernin3,6,7, Caius G Radu3,7, Katharina Lückerath10,6,7, Roger Slavik3. 1. Atreca Inc., South San Francisco, California. 2. AstraZeneca, Chemical Biology Group, Waltham, Massachusetts. 3. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California. 4. Department of Translational Medicine, Division of Urological Cancers, Skåne University Hospital Malmö, Lund University, Lund, Sweden. 5. School of Electronics, Electrical Engineering, and Computer Science, Queen's University Belfast, Belfast, United Kingdom. 6. Department of Urology, Institute of Urologic Oncology, UCLA, Los Angeles, California; and. 7. Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California. 8. Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany. 9. Clinic for Nuclear Medicine, Technical University Munich, Munich, Germany. 10. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California; klueckerath@mednet.ucla.edu.
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.
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.
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