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

First Author	Najumudeen AK	Year	2021
Journal	Nat Genet	Volume	53
Issue	1	Pages	16-26
PubMed ID	33414552	Mgi Jnum	J:302321
Mgi Id	MGI:6508163	Doi	10.1038/s41588-020-00753-3
Citation	Najumudeen AK, et al. (2021) The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nat Genet 53(1):16-26

abstractText

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.

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43 Authors

Barry ST,
Hedley A,
Dexter A,
Hall H,
Leach JDG,
Knight JRP,
Najumudeen AK,
Solovyev D,
Ceteci F,
Gilroy K,
Steven RT,
Hamm G,
Vlahov N,
Sumpton D,
Sansom OJ,
Bushell M,
Takats Z,
Goodwin RJA,
Malla SB,
Lewis DY,
Bunch J,
Rodriguez-Blanco G,
Nikula CJ,
Mrowinska A,
Gay DM,
Brown G,
CRUK Rosetta Grand Challenge Consortium.,
Fey SK,
Clark W,
Critchlow SE,
Dunne PD,
Ridgway RA,
Mackay GM,
Johnson ER,
Gottlieb E,
Strathdee D,
Nixon C,
Malviya G,
Murta T,
Race AM,
Campbell AD,
Jackstadt R,
Tardito S

23 Bio Entities

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