Dataset Information

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

ABSTRACT: Purpose: Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-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. Experimental Design: Therapeutic efficacy of PSMA-RLT was assessed by tumor volume measurements, time to progression, and survival in C4-2 or C4-2 TP53-knockout tumor-bearing Nod scid gamma mice. Two days post-RLT, the (phospho)proteome was analyzed by mass spectrometry. Results: PSMA-RLT significantly improved disease control in a dose-dependent manner. (Phospho)proteomic datasets revealed activation of genotoxic stress response pathways, including deregulation of DNA damage/replication stress response, TP53, androgen receptor, PI3K/AKT, and MYC signaling. C4-2 TP53-knockout tumors were less sensitive to PSMA-RLT than parental counterparts, supporting a role for TP53 in mediating RLT responsiveness. Conclusions: 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.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Caius Radu

PROVIDER: MSV000086408 | MassIVE | Wed Nov 04 10:02:00 GMT 2020

REPOSITORIES: MassIVE

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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 AD Capri Joseph R JR Meyer Catherine A L CAL Le Thuc M TM Evans-Axelsson Susan L SL Current Kyle K Lennox Mark M Mona Christine E CE Fendler Wolfgang P WP Calais Jeremie J Eiber Matthias M Dahlbom Magnus M Czernin Johannes J Radu Caius G CG Lückerath Katharina K Slavik Roger R

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20201204 7

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, ...[more]

PMID: 33277393

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