Targeting Metabolic Adaptation to Treat TP53-mutated Lethal Prostate Cancer

Inactivation of TP53 by missense mutation occurs frequently in castration-resistant prostate cancers (CRPC) with poor clinical outcomes, making it an attractive therapeutic target. However, to date there are no effective treatments that specifically target tumors with TP53 mutations. Thus, there is an urgent need to identify and target vulnerabilities that perpetuate disease progression and treatment resistance resulting from gain-of-function (GOF) mutant p53. Hypothesis, Specific Aims, and Study Design: Our preliminary results using patient samples, genetically engineered mice (GEM), PDX models and cell lines show that high expression of asparagine synthetase (ASNS, the enzyme catalyzing the synthesis of asparagine), and increased asparagine availability are features of CRPC with missense hotspot mutations in the TP53 gene. Notably, prostate tumors with GOF mutant TP53 are sensitive to depletion of asparagine by knockdown of ASNS and asparaginase treatment to deplete the intracellular and extracellular sources of L-asparaginase respectively. However, there are no clinical-stage ASNS inhibitors yet available. Nonetheless, glutaminase inhibition may also deplete intracellular asparagine. Indeed, we obtained preliminary evidence that treatment with the clinical-stage glutaminase (GLS) inhibitor CB-839 and the FDA-approved drug L-asparaginase, significantly depleted asparagine and suppressed the growth of TP53- mutant CRPC. We hypothesize that the reliance of TP53-mutant prostate cancer on asparagine metabolism creates a potential vulnerability that can be exploited to improve prostate cancer outcomes.