@article{3ce54fdeadf74e919d398fc5daec6ef4,
title = "The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer",
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.",
author = "{CRUK Rosetta Grand Challenge Consortium} and Najumudeen, {Arafath K.} and Fatih Ceteci and Fey, {Sigrid K.} and Gregory Hamm and Steven, {Rory T.} and Holly Hall and Nikula, {Chelsea J.} and Alex Dexter and Teresa Murta and Race, {Alan M.} and David Sumpton and Nikola Vlahov and Gay, {David M.} and Knight, {John R.P.} and Rene Jackstadt and Leach, {Joshua D.G.} and Ridgway, {Rachel A.} and Johnson, {Emma R.} and Colin Nixon and Ann Hedley and Kathryn Gilroy and William Clark and Malla, {Sudhir B.} and Dunne, {Philip D.} and Giovanny Rodriguez-Blanco and Critchlow, {Susan E.} and Agata Mrowinska and Gaurav Malviya and Dmitry Solovyev and Gavin Brown and Lewis, {David Y.} and Mackay, {Gillian M.} and Douglas Strathdee and Saverio Tardito and Eyal Gottlieb and Andrew Campbell and Race, {Alan M.} and Ian Gilmore and Greg McMahon and Paul Grant and Bin Yan and Taylor, {Adam J.} and Efstathios Elia and Spencer Thomas and Catherine Munteanu and Ala Al-Afeef and Amy Burton and Vorng, {Jean Luc} and Xavier Loizeau and Weiwei Zhou",
note = "Funding Information: We are grateful to the CRUK Beatson Institute Central Services, Histology Service, the Transgenic Technology Laboratory and the Biological Services Unit for technical support and all members of the Sansom lab for discussion of the data and manuscript. O.J.S. was supported by grants from CRUK (A21139, A12481 and A17196) and the ERC (311301). A.K.N, G.H., R.T.S., C.J.N., T.M., A.M.R., A.D., Z.T., R.J.A.G. and J.B. were supported by the CRUK Rosetta Grand Challenge grant (A25045 to J.B. and O.J.S.). F.C., R.A.R., D. Sumpton, C.N., G.M.M., E.G., S. Tardito and A.D.C. were supported by the CRUK Beatson Institute core grant (A17196 to O.J.S.). S.K.F. was supported by Pancreatic Cancer UK Future Leaders Academy (to O.J.S.). N.V. was supported by the Wellcome Trust (201487 to O.J.S.). D.M.G. was supported by an ERC grant (311301 to O.J.S.). J.R.P.K. was supported by a CRUK Programme Award (A24388 to M.B. and O.J.S.). R.J. was supported by a Marie Sk{\l}odowska-Curie Actions postdoctoral fellowship (ERC 659666). J.D.G.L. was supported by an MRC Clinical Research Training Fellowship (MR/ N021800/1). K.G. was supported by the CRUK Grand Challenge Specificancer Grand Challenge Consortium (A29055 to O.J.S.). Holly Hall. was supported by BB/N017005/1. Funding Information: M.B. was supported by the CRUK Beatson Institute core grant 29252. S.B.M. and P.D.D. were supported by a CRUK Early Detection award (C50686/A29834). GLS inhibitor (described in ref. 44) was provided by AstraZeneca and CRUK Therapeutic Discovery Laboratories. We thank M. Pasca di Magliano (University of Michigan) for providing us with the doxycycline-inducible KrasG12D mouse. We thank A. Dannhorn (AstraZeneca) for establishment of the MSI sample preparation method and A. Dannhorn and N. Strittmatter (AstraZeneca) for DESI optimization. We thank the members of the CRUK Rosetta Grand Challenge Consortium for participating in this study. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = jan,
day = "7",
doi = "10.1038/s41588-020-00753-3",
language = "English",
volume = "53",
pages = "16--26",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Springer Nature",
number = "1",
}