The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer

Oncogenic KRAS mutations and inactivation of the APC tumour suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus upon downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, rendering them 'addicted' to glutamine supporting proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino-acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via mTORC1 inhibition, cooperates with Slc7a5 deletion to abrogate growth of established KRAS-mutant tumours. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC. Overall design: RNA samples were prepared from 1) small intestinal tissue samples of 3 independent animals per genotype or 2) from small intestinal tissue samples of 4 indepdent animals treated with vehicle or rapamycin per group or from 3 Apc iKras organoid tumour lines isolated from intestinal tissue of 3 independent animals per group treated with or without doxycycline for 24 or 48h. Each experimental setting includes a control group of 3 animals/lines - these are samples (tissue) or (organoid).