학술논문
The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer
Document Type
Report
Author
Najumudeen, Arafath K.; Ceteci, Fatih; Fey, Sigrid K.; Hamm, Gregory; Steven, Rory T.; Hall, Holly; Nikula, Chelsea J.; Dexter, Chelsea J.; Dexter, Alex; Murta, Teresa; Race, Alan M.; Sumpton, David; Vlahov, Nikola; Gay, David M.; Knight, John R.P.; Jackstadt, Rene; Leach, Joshua D.G.; Ridgway, Rachel A.; Johnson. Emma R.; Nixon, Colin; Hedley, Ann; Gilroy, Kathryn; Clark, William; Malla, Sudhir B.; Dunne, Philip D.; Rodriguez-Blanco, Giovanny; Critchlow, Susan E.; Mrowinska, Agata; Malviya, Gaurav; Solovyev, Dmitry; Brown, Gavin; Lewis, David Y.; Mackay, Gillian M.; Strathdee, Douglas; Tardito, Saverio; Gottlieb, Eyal; Campbell, Andrew; Najumudeen, Arafath; Gilmore, Ian; McMahon, Greg; Afeef, Paul Ala Al-; Burton, Amy; Vorng, Jean-Luc; Loizeau, Xavier; Zhou, Weiwei; Nasif, Ammar; Gonzalez, Ariadna; Koquna, Hanifa; Metodiev, Martin; Kyriazi, Melina; Zhang, Junting; Zeiger, Lucas; Vande-Voorde, Johan; Morton, Jennifer; Soloviev, Dmitry; Wu, Vincen; Xiang, Yuchen; McGill, Daniel; Maneta-Stravrakaki, Stefania; Mistry, Jaynisha; Kazanc, Emine; Yuneva, Mariia; Panina, Yulia; Nanda, Chandan Seth; Kreuzaler, Peter; Ghanate, Avinash; Ling, Stephanie; Richings, Jack; Brindle, Kevin; Tsyben, Anastasia; Poulogiannis, George; Gupta, Amit; Tripp, Aurelien; Karali, Evi; Koundouros, Nikolaos; Tsalikis, Thanasis; Marshall, John; Garrett, Magali; Hall, Harry
Source
Nature Genetics. January 2021, Vol. 53 Issue 1, p16, 11 p.
Subject
Language
English
ISSN
1061-4036
Abstract
Author(s): Arafath K. Najumudeen [sup.1] , Fatih Ceteci [sup.1] [sup.15] , Sigrid K. Fey [sup.1] [sup.2] , Gregory Hamm [sup.3] , Rory T. Steven [sup.4] , Holly Hall [sup.1] , [...]
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.
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.