TY - JOUR
T1 - Mechanisms of Resistance to Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy in a Mouse Model of Prostate Cancer
AU - Stuparu, Andreea D.
AU - Capri, Joseph R.
AU - Meyer, Catherine A.L.
AU - Le, Thuc M.
AU - Evans-Axelsson, Susan L.
AU - Current, Kyle
AU - Lennox, Mark
AU - Mona, Christine E.
AU - Fendler, Wolfgang P.
AU - Calais, Jeremie
AU - Eiber, Matthias
AU - Dahlbom, Magnus
AU - Czernin, Johannes
AU - Radu, Caius G.
AU - Lückerath, Katharina
AU - Slavik, Roger
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
KW - DNA damage response
KW - prostate cancer
KW - proteomics/phosphoproteomics
KW - [177Lu]Lu-PSMA
KW - [225Ac]Ac-PSMA
U2 - 10.2967/jnumed.120.256263
DO - 10.2967/jnumed.120.256263
M3 - Article
C2 - 33277393
AN - SCOPUS:85108555828
SN - 0161-5505
VL - 62
SP - 989
EP - 995
JO - Journal of nuclear medicine : official publication, Society of Nuclear Medicine
JF - Journal of nuclear medicine : official publication, Society of Nuclear Medicine
IS - 7
ER -