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

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. <b>Methods:</b> Therapeutic efficacy of PSMA RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 <i>TP53</i>^<i>-/-</i> tumor-bearing nonobese diabetic <i>scid</i> γ-mice. Two days after RLT, the proteome and phosphoproteome were analyzed by mass spectrometry. <b>Results:</b> 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 <i>TP53</i>^<i>-/-</i> tumors were less sensitive to PSMA RLT than were parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. <b>Conclusion:</b> 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.