PT  - JOURNAL ARTICLE
AU  - Andreea D. Stuparu
AU  - Joseph R. Capri
AU  - Catherine A.L. Meyer
AU  - Thuc M. Le
AU  - Susan L. Evans-Axelsson
AU  - Kyle Current
AU  - Mark Lennox
AU  - Christine E. Mona
AU  - Wolfgang P. Fendler
AU  - Jeremie Calais
AU  - Matthias Eiber
AU  - Magnus Dahlbom
AU  - Johannes Czernin
AU  - Caius G. Radu
AU  - Katharina Lückerath
AU  - Roger Slavik
TI  - Mechanisms of Resistance to Prostate-Specific Membrane Antigen–Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer
AID  - 10.2967/jnumed.120.256263
DP  - 2021 Jul 01
TA  - Journal of Nuclear Medicine
PG  - 989--995
VI  - 62
IP  - 7
4099  - http://jnm.snmjournals.org/content/62/7/989.short
4100  - http://jnm.snmjournals.org/content/62/7/989.full
SO  - J Nucl Med2021 Jul 01; 62
AB  - 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.