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

Najumudeen, A. K. et al. (2021) The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nature Genetics, 53, pp. 16-26. (doi: 10.1038/s41588-020-00753-3) (PMID:33414552)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tardito, Dr Saverio and Clark, Mr William and Fey, Sigrid and Gottlieb, Professor Eyal and Sumpton, Mr David and Mackay, Dr Gillian and Mrowinska, Ms Agata and Lewis, Dr David and Gilroy, Dr Kathryn and Leach, Dr Joshua and Nixon, Mr Colin and Gay, David and Strathdee, Mr Douglas and Goodwin, Dr Richard and Ridgway, Dr Rachel and Ceteci, Dr Fatih and Malviya, Dr Gaurav and Sansom, Professor Owen and Bushell, Professor Martin and Campbell, Dr Andrew and Johnson, Ms Emma
• Authors: Najumudeen, A. K., Ceteci, F., Fey, S. K., Hamm, G., Steven, R. T., Hall, H., Nikula, C. J., Dexter, A., Murta, T., Race, A. M., Sumpton, D., Vlahov, N., Gay, D. M., Knight, J. R.P., Jackstadt, R., Leach, J. D.G., Ridgway, R. A., Johnson, E. R., Nixon, C., Hedley, A., Gilroy, K., Clark, W., Malla, S. B., Dunne, P. D., Rodriguez-Blanco, G., Critchlow, S. E., Mrowinska, A., Malviya, G., Solovyev, D., Brown, G., Lewis, D. Y., Mackay, G. M., Strathdee, D., Tardito, S., Gottlieb, E., Takats, Z., Barry, S. T., Goodwin, R. J.A., Bunch, J., Bushell, M., Campbell, A. D., and Sansom, O. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature Genetics
• Publisher: Nature Research
• ISSN: 1061-4036
• ISSN (Online): 1546-1718