Abstract 1712: Targeting asparagine dependency as a therapy for TP53-mutated castration-resistant prostate cancer

Abstract

Abstract Background: The 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 gain-of-function (GOF) mutants. Thus, there is an urgent need to identify and target vulnerabilities that perpetuate disease progression and treatment resistance resulting from TP53 GOF mutants. Methods: We performed RNA sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics on GEM and PDX CRPC models with or without TP53 GOF mutations. Our findings were validated using genetic and pharmacologic approaches in relevant in vitro and in vivo models. We assessed the effect of L-asparaginase (ASNase) or/and glutaminase (GLS) inhibitor CB-839 in cell lines, organoids and PDX models. Tumors were characterized by histology and immunohistochemistry for relevant markers. Results: Using transcriptomic and metabolomic analyses, we show here that TP53-mutated prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS, the enzyme catalyzing the synthesis of asparagine). Mechanistically, TP53 GOF mutations transcriptionally activate ASNS expression, directly as well as via ATF4, driving de novo asparagine biosynthesis to support CRPC growth. TP53-mutated CRPC cells are sensitive to asparagine restriction by knockdown of ASNS and L-asparaginase treatment to deplete the intracellular and extracellular sources of asparagine respectively. This effect was rescued by asparagine addition. Notably, pharmacological inhibition of intracellular asparagine biosynthesis using a glutaminase (GLS) inhibitor and depletion of extracellular asparagine with L-asparaginase significantly reduced asparagine production and effectively impaired CRPC growth. Conclusions: This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 GOF mutations, providing a rationale for co-targeting intracellular and extracellular asparagine production to treat these lethal prostate cancers. Citation Format: Young A Yoo. Targeting asparagine dependency as a therapy for TP53-mutated castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1712.