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

Andreea D. Stuparu, Joseph R. Capri, Catherine A.L. Meyer, Thuc M. Le, Susan L. Evans-Axelsson, Kyle Current, Mark Lennox, Christine E. Mona, Wolfgang P. Fendler, Jeremie Calais, Matthias Eiber, Magnus Dahlbom, Johannes Czernin, Caius G. Radu, Katharina Lückerath, Roger Slavik

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review


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.

Sidor (från-till)989-995
Antal sidor7
TidskriftJournal of nuclear medicine : official publication, Society of Nuclear Medicine
StatusPublished - 2021 juli 1

Ämnesklassifikation (UKÄ)

  • Cancer och onkologi


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