The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer
Authors listAK Najumudeen F Ceteci SK Fey G Hamm RT Steven H Hall CJ Nikula A Dexter T Murta AM Race D Sumpton N Vlahov DM Gay JRP Knight R Jackstadt JDG Leach RA Ridgway ER Johnson C Nixon A Hedley K Gilroy W Clark SB Malla PD Dunne G Rodriguez-Blanco SE Critchlow A Mrowinska G Malviya D Solovyev G Brown DY Lewis GM Mackay D Strathdee S Tardito E Gottlieb CRUK Rosetta Grand Challenge Consortium A Campbell A Najumudeen AM Race I Gilmore G McMahon P Grant B Yan AJ Taylor E Elia S Thomas C Munteanu A Al-Afeef A Burton JL Vorng X Loizeau W Zhou A Nasif A Gonzalez H Koquna M Metodiev M Kyriazi J Zhang L Zeiger J Vande-Voorde J Morton D Soloviev V Wu Y Xiang D McGill S Maneta-Stravrakaki J Mistry E Kazanc Mariia Yuneva Yulia Panina CS Nanda Peter Kreuzaler Avinash Ghanate S Ling J Richings K Brindle A Tsyben G Poulogiannis A Gupta A Tripp E Karali N Koundouros T Tsalikis J Marshall M Garrett H Hall Z Takats ST Barry RJA Goodwin J Bunch M Bushell AD Campbell OJ Sansom
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© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support 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 the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
Journal Nature Genetics
Issue number 1