Abstract
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, respectively, and cell viability was rescued by Asn addition. Notably, pharmacological inhibition of intracellular Asn biosynthesis using a glutaminase inhibitor and depletion of extracellular Asn with L-asparaginase significantly reduced Asn production and effectively impaired CRPC growth. This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 alterations, providing a rationale for targeting Asn production to treat these lethal prostate cancers.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3004-3022 |
| Number of pages | 19 |
| Journal | Cancer Research |
| Volume | 84 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 15 2024 |
Funding
We thank all the S.A. Abdulkadir lab members for discussion. We thank Dr. Matthew J. Schipma, Priyam Patel, and Brian Wray at the NUSeq Facility for RNA-seq and ATAC-seq data analysis. Metabolomics services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. This research was supported by National Cancer Institute grant P50CA180995 and Polsky Urological Cancer Research Institute. This work was also supported in part by the Urology Care Foundation Research Scholar Award Program and by Robert J. Krane, MD, to Y.A. Yoo. Y.A. Yoo reports grants from Urology Care Foundation during the conduct of the study. B. Lackie reports grants from NIH during the conduct of the study and personal fees from Amgen outside the submitted work. M.I. Truica reports grants from NIH during the conduct of the study. S.A. Abdulkadir reports grants from National Cancer Institute and grants from Polsky Urologic Cancer Research Institute during the conduct of the study. No disclosures were reported by the other authors.
ASJC Scopus subject areas
- Oncology
- Cancer Research
