Abstract SY22-02: Metabolic vulnerability of PTEN mutant cancer

Abstract

Abstract Signaling pathways that act as drivers of cancer cell growth and proliferation activate metabolic pathways required to generate the building blocks required for cell doubling. Loss of PTEN activates PI3K, AKT and mTOR to stimulate glucose and glutamine flux to allow DNA replication. One of the metabolic pathways that is activated after deletion of both alleles of PTEN is the de novo pyrimidine synthesis pathway. PTEN null cells show evidence of increased DNA replication and low levels of damage at replication forks that can be rescued by providing supplementary uridine. Interruption of de novo pyrimidine synthesis with an inhibitor of dihydroorotate dehydrogenase (DHODH) increased DNA damage at replication forks of PTEN null cells that ultimately led to chromosome breaks detected in mitosis and cell death. This cellular vulnerability to inhibition of DHODH was rescued with uridine, demonstrating the specificity of the effect. Exploration of the mechanism that led to vulnerability of PTEN null cells demonstrated that it was due to defective ATR signaling at replication forks that was a consequence of activated AKT, which phosphorylate and attenuate TOPBP1 and CHK1. Complementation of PTEN null cells with mutants of TOPBP1 and CHK1 that cannot be phosphorylated by AKT rescued the cells from DNA damage and cell death due to inhibition of DHODH. Tumor cell lines lacking PTEN tended to be more sensitive to DHODH inhibition than PTEN wild type cells were. In conclusion, the attenuated ATR signaling and increased flux of nucleotides to newly synthesized DNA at replication forks makes PTEN mutant cells vulnerable to disruption of de novo pyrimidine synthesis. Citation Format: Ramon E. Parsons. Metabolic vulnerability of PTEN mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY22-02.