Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer

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 ofmore 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 TP532/2 tumor-bearing nonobese diabetic scid g-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 andphosphoproteomedatasets revealedactivationof genotoxic stress response pathways, including deregulation ofDNA damage/replication stress response, TP53, androgen receptor, phosphatidylinositol-3- kinase/AKT, andMYCsignaling.C4-2TP532/2 tumorswere less sensitive to PSMARLT thanwereparental counterparts, supporting a role for TP53 inmediatingRLT responsiveness.Conclusion:Weidentified signaling alterations that may mediate resistance to PSMA RLT in a PCa mousemodel. Our data enable the development of rational synergistic RLT-combination therapies to improve outcomes for PCa patients.