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Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that  PIK3CA  mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells,  PIK3CA  mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregulates  GPT2  gene expression through an AKT-independent, PDK1–RSK2–ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with  PIK3CA  mutations, but not with WT  PIK3CA . Together, these data establish oncogenic  PIK3CA  mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring  PIK3CA  mutations.

Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer