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

Stuparu, Andreea D. ; Capri, Joseph R. ; Meyer, Catherine A.L. ; Le, Thuc M. ; Evans-Axelsson, Susan L. LU orcid ; Current, Kyle ; Lennox, Mark ; Mona, Christine E. ; Fendler, Wolfgang P. and Calais, Jeremie , et al. (2021) In Journal of nuclear medicine : official publication, Society of Nuclear Medicine 62(7). p.989-995
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. 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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DNA damage response, prostate cancer, proteomics/phosphoproteomics, [177Lu]Lu-PSMA, [225Ac]Ac-PSMA
in
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
volume
62
issue
7
pages
7 pages
publisher
Society of Nuclear Medicine
external identifiers
  • scopus:85108555828
  • pmid:33277393
ISSN
0161-5505
DOI
10.2967/jnumed.120.256263
language
English
LU publication?
yes
id
e427bbf2-26d2-4348-8902-2580ec09ceb3
date added to LUP
2022-03-18 16:22:02
date last changed
2022-06-29 18:33:46
@article{e427bbf2-26d2-4348-8902-2580ec09ceb3,
  abstract     = {{<p>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.</p>}},
  author       = {{Stuparu, Andreea D. and Capri, Joseph R. and Meyer, Catherine A.L. and Le, Thuc M. and Evans-Axelsson, Susan L. and Current, Kyle and Lennox, Mark and Mona, Christine E. and Fendler, Wolfgang P. and Calais, Jeremie and Eiber, Matthias and Dahlbom, Magnus and Czernin, Johannes and Radu, Caius G. and Lückerath, Katharina and Slavik, Roger}},
  issn         = {{0161-5505}},
  keywords     = {{DNA damage response; prostate cancer; proteomics/phosphoproteomics; [177Lu]Lu-PSMA; [225Ac]Ac-PSMA}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{7}},
  pages        = {{989--995}},
  publisher    = {{Society of Nuclear Medicine}},
  series       = {{Journal of nuclear medicine : official publication, Society of Nuclear Medicine}},
  title        = {{Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer}},
  url          = {{http://dx.doi.org/10.2967/jnumed.120.256263}},
  doi          = {{10.2967/jnumed.120.256263}},
  volume       = {{62}},
  year         = {{2021}},
}