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

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)989-995
Number of pages7
JournalJournal of Nuclear Medicine
Volume62
Issue number7
DOIs
StatePublished - 1 Jul 2021

Keywords

  • DNA damage response
  • [177Lu]Lu-PSMA;prostatecancer;proteomics/ phosphoproteomics
  • [225Ac]Ac-PSMA

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