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

Autor: Najumudeen AK; Cancer Research UK Beatson Institute, Glasgow, UK., Ceteci F; Cancer Research UK Beatson Institute, Glasgow, UK.; Georg Speyer Haus Institute for Tumour Biology and Experimental Therapy, Paul-Ehrlich-Straße, Frankfurt, Germany., Fey SK; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Hamm G; Imaging and data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK., Steven RT; National Physical Laboratory, Teddington, Middlesex, UK., Hall H; Cancer Research UK Beatson Institute, Glasgow, UK., Nikula CJ; National Physical Laboratory, Teddington, Middlesex, UK., Dexter A; National Physical Laboratory, Teddington, Middlesex, UK., Murta T; National Physical Laboratory, Teddington, Middlesex, UK., Race AM; Imaging and data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK.; Institute of Medical Bioinformatics and Biostatistics, University of Marburg, Marburg, Germany., Sumpton D; Cancer Research UK Beatson Institute, Glasgow, UK., Vlahov N; Cancer Research UK Beatson Institute, Glasgow, UK., Gay DM; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.; Københavns Universitet, BRIC, Copenhagen, Denmark., Knight JRP; Cancer Research UK Beatson Institute, Glasgow, UK., Jackstadt R; Cancer Research UK Beatson Institute, Glasgow, UK.; Heidelberg Institute for Stem Cell Technology and Experimental Medicine gGmbH (HI-STEM), Division of Cancer Progression and Metastasis, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany., Leach JDG; Cancer Research UK Beatson Institute, Glasgow, UK., Ridgway RA; Cancer Research UK Beatson Institute, Glasgow, UK., Johnson ER; Cancer Research UK Beatson Institute, Glasgow, UK., Nixon C; Cancer Research UK Beatson Institute, Glasgow, UK., Hedley A; Cancer Research UK Beatson Institute, Glasgow, UK., Gilroy K; Cancer Research UK Beatson Institute, Glasgow, UK., Clark W; Cancer Research UK Beatson Institute, Glasgow, UK., Malla SB; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Dunne PD; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Rodriguez-Blanco G; Cancer Research UK Beatson Institute, Glasgow, UK., Critchlow SE; Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK., Mrowinska A; Cancer Research UK Beatson Institute, Glasgow, UK., Malviya G; Cancer Research UK Beatson Institute, Glasgow, UK., Solovyev D; Cancer Research UK Beatson Institute, Glasgow, UK., Brown G; Cancer Research UK Beatson Institute, Glasgow, UK., Lewis DY; Cancer Research UK Beatson Institute, Glasgow, UK., Mackay GM; Cancer Research UK Beatson Institute, Glasgow, UK., Strathdee D; Cancer Research UK Beatson Institute, Glasgow, UK., Tardito S; Cancer Research UK Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Gottlieb E; Cancer Research UK Beatson Institute, Glasgow, UK.; The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel., Takats Z; Department of Metabolism, Imperial College London, London, UK., Barry ST; Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK., Goodwin RJA; Imaging and data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK.; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Bunch J; National Physical Laboratory, Teddington, Middlesex, UK., Bushell M; Cancer Research UK Beatson Institute, Glasgow, UK., Campbell AD; Cancer Research UK Beatson Institute, Glasgow, UK., Sansom OJ; Cancer Research UK Beatson Institute, Glasgow, UK. o.sansom@beatson.gla.ac.uk.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. o.sansom@beatson.gla.ac.uk.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2021 Jan; Vol. 53 (1), pp. 16-26. Date of Electronic Publication: 2021 Jan 07.
DOI: 10.1038/s41588-020-00753-3
Abstrakt: 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.
Databáze: MEDLINE
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