Abstract 1125: Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers

Abstract Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is the most frequently mutated oncogene in human cancers. However, whether PIK3CA mutations reprogram cancer metabolism is an important unaddressed question. Here we show that oncogenic PIK3CA mutations reprogram glutamine metabolism by up-regulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, thereby rendering them addicted to glutamine. We demonstrated that induction of GPT2 by mutant p110α is necessary and sufficient to render CRC cells addicted to glutamine. Moreover, aminooxyacetate, which inhibits enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumor growth of CRCs with PIK3CA mutations, but not CRCs with WT PIK3CA. Thus our data suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harboring PIK3CA mutations. Mutant p110α up-regulates GPT2 gene expression through an AKT-independent PDK1-RSK2-ATF4 signaling axis. We showed that ATF4 is a transcription factor that activates GPT2 gene expression. We further demonstrated that mutant p110α activates RSK2 kinase through PDK1. Activated RSK2 then phosphorylates ATF4 at the serine residue 245, which in turn recruits deubiquitinase USP8 and protects ATF4 from ubiquitin-mediated degradation. Lastly, using [13C5-]glutamine isotope-tracing technology, we showed that PIK3CA mutant CRCs convert more glutamine to α-keto-glutarate to replenish the tricarboxylic acid (TCA) cycle to generate ATP. Together, our data establish oncogenic PIK3CA mutations as a cause of glutamine addiction in CRCs. Citation Format: Yujun Hao, Yardena Samuels, Qingling Li, Dawid Krokowski, Henri Brunengraber, Maria Hatzoglou, Guo-Fang Zhang, Bert Vogelstein, Zhenghe Wang. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1125. doi:10.1158/1538-7445.AM2015-1125