Abstract
<div>Abstract<p><i>TP53</i> tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target <i>TP53</i> alterations. Using transcriptomic and metabolomic analyses, we have shown here that <i>TP53</i>-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 <i>TP53</i> transcriptionally activated ASNS expression, directly and via mTORC1-mediated ATF4 induction, driving <i>de novo</i> Asn biosynthesis to support CRPC growth. <i>TP53</i>-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 <i>TP53</i> alterations, providing a rationale for targeting Asn production to treat these lethal prostate cancers.</p><p><b>Significance: </b><i>TP53</i>-mutated castration-resistant prostate cancer is dependent on asparagine biosynthesis due to upregulation of ASNS and can be therapeutically targeted by approaches that deplete intracellular and extracellular asparagine.</p></div>
Published Version
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