Journal Article

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

Race, Alan M., Barry, Simon T., Nikula, Chelsea J., Hedley, Ann, Hamm, Gregory, Critchlow, Susan E., Solovyev, Dmitry, Brown, Gavin, Tardito, Saverio, Gay, David M., Leach, Joshua D. G., Fey, Sigrid K., Dexter, Alex, Ridgway, Rachel A., Bunch, Josephine, Campbell, Andrew D., Jackstadt, Rene, Takats, Zoltan, Sumpton, David, Johnson, Emma R., Mrowinska, Agata, Najumudeen, Arafath K., Bushell, Martin, Rodriguez-Blanco, Giovanny, Hall, Holly, Malla, Sudhir B., Murta, Teresa, Dunne, Philip D., Strathdee, Douglas, Malviya, Gaurav, Gottlieb, Eyal, Ceteci, Fatih, Steven, Rory T., Nixon, Colin, Lewis, David Y., Mackay, Gillian M., Goodwin, Richard J. A., Sansom, Owen J., Clark, William, Gilroy, Kathryn, Knight, John R. P., Vlahov, Nikola

2021

Overview

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. Colorectal tumors with mutated KRAS and APC require the amino acid transporter SLC7A5 to drive tumorigenesis. Mechanistically, SLC7A5 drives transcriptional and metabolic reprogramming by maintaining intracellular amino acid levels, leading to enhanced protein synthesis.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/100 / 13/106 / 38/91 / 5' Untranslated Regions - genetics / 631/67 / 631/67/1504 / 631/67/1504/1885 / 631/67/1504/1885/1393 / 631/67/395 / 64/60 / 82/51 / 82/58 / 82/80 / Adenomatous polyposis coli / Agriculture / Amino Acid Transport System ASC - metabolism / Amino acids / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Carcinogenesis - pathology / Carrier proteins / Cell growth / Cell Proliferation / Colorectal cancer / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Epithelium / Gene expression / Gene Expression Regulation, Neoplastic / Gene Function / Genetic aspects / Glucose / Glutamine / Glutamine - metabolism / Growth / Health aspects / Human Genetics / Humans / Inactivation / Intestinal Mucosa - metabolism / Intestinal Mucosa - pathology / Intestine / K-Ras protein / Kaplan-Meier Estimate / Kinases / Large Neutral Amino Acid-Transporter 1 - metabolism / Life Sciences / Mechanistic Target of Rapamycin Complex 1 - metabolism / Metabolic rate / Metabolism / Metabolites / Metastases / Mice / Mice, Inbred C57BL / Minor Histocompatibility Antigens - metabolism / Mutants / Mutation / Mutation (Biology) / Mutation - genetics / Neoplasm Metastasis / Oncogenes / Physiological aspects / Protein biosynthesis / Protein synthesis / Proteins / Proto-Oncogene Proteins p21(ras) - genetics / RNA, Messenger - genetics / RNA, Messenger - metabolism / Signal Transduction / TOR Serine-Threonine Kinases - metabolism / Transcription activation / Tumor suppressor genes / Tumorigenesis / Tumors