The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade

Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis to glutamate by the mitochondrial enzyme glutaminase (GLS). However, this metabolic addiction can be lost in the tumor microenvironment (TME), rendering GLS inhibitors ineffective in the clinic. Here, we show that seemingly glutamine-addicted breast cancer cells ultimately adapt to chronic glutamine starvation, or targeted GLS inhibition, via the AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine itself, but a-ketoglutarate (a-KG). Mechanistically, we find that the phylogenetically distinct transaminase phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained a-KG production when glutamate is severely depleted. Breast cancer cells with intrinsic or acquired resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied a-KG. Accordingly, pharmacological disruption of the SSP prevents adaptation to glutamine blockade, yielding a potent drug synergism that abolishes breast tumor growth in vivo. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumor growth in a particular nutrient environment. This in turn has practical consequences for therapies targeting cancer metabolism.