biostudies-literatureYoo YANational Cancer Institute (NCI)Urology Care FoundationNational Cancer InstituteUrology Care Foundation (UCF)NCI NIH HHSNIH HHS3004-3022https://www.ebi.ac.uk/biostudies/studies/S-EPMC11405136biostudies-literatureUnknown84(18)TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we have shown here that TP53-altered prostate cancer exhibits an increased dependency on asparagine (Asn) and overexpresses Asn synthetase (ASNS), the enzyme catalyzing the synthesis of Asn. Mechanistically, the loss or mutation of TP53 transcriptionally activated ASNS expression, directly and via mTORC1-mediated ATF4 induction, driving de novo Asn biosynthesis to support CRPC growth. TP53-altered CRPC cells were sensitive to Asn restriction by knockdown of ASNS or L-asparaginase treatment to deplete the intracellular and extracellular sources of Asn, rCancer researchAsparagine Dependency Is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer.PMC11405136P50 CA180995S10 OD027016P50CA180995Yoo YALackie BSagar VChandel NSUnno KTruica MIGuo QYang WQuan SRodriguez YChalmers ZRAbdulkadir SADufficy MFfalseAsparagine Dependency Is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer.TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we have shown here that TP53-altered prostate cancer exhibits an increased dependency on asparagine (Asn) and overexpresses Asn synthetase (ASNS), the enzyme catalyzing the synthesis of Asn. Mechanistically, the loss or mutation of TP53 transcriptionally activated ASNS expression, directly and via mTORC1-mediated ATF4 induction, driving de novo Asn biosynthesis to support CRPC growth. TP53-altered CRPC cells were sensitive to Asn restriction by knockdown of ASNS or L-asparaginase treatment to deplete the intracellular and extracellular sources of Asn, r2024-01-01T00:00:00Z2024 Sep2026-06-01T05:59:53.377Z2025-04-04T09:07:18.046ZS-EPMC114051363895933510.1158/0008-5472.CAN-23-291010.1158/0008-5472.can-23-2910