Mechanisms of Resistance to Prostate-Specific Membrane Antigen–Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer
Andreea D. Stuparu, Joseph Capri, Catherine Meyer, Thuc Le, Susan Evans‐Axelsson, Kyle Current, Mark Lennox, Christine E. Mona, Wolfgang P. Fendler, Jérémie Calais, Matthias Eiber, Magnus Dahlbom, Johannes Czernin, Caius G. Radu, Katharina Lückerath, Roger Slavik
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><sup><i>−/−</i></sup> 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><sup><i>−/−</i></sup> 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.