1. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer
- Author
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Owen J. Sansom, John R. P. Knight, Simon T. Barry, Rachel A. Ridgway, David Sumpton, Rory T. Steven, Giovanny Rodriguez-Blanco, Eyal Gottlieb, Gaurav Malviya, William C. Clark, Douglas Strathdee, Emma R. Johnson, Holly Hall, Alex Dexter, Teresa Murta, David Y. Lewis, Saverio Tardito, Gregory Hamm, Gavin Brown, Colin Nixon, Kathryn Gilroy, Zoltan Takats, Sudhir B Malla, Dmitry Solovyev, Sigrid K. Fey, Fatih Ceteci, Gillian M. Mackay, Susan E. Critchlow, Ann Hedley, Nikola Vlahov, Alan M. Race, Martin Bushell, Andrew D. Campbell, Arafath Kaja Najumudeen, Richard J. A. Goodwin, Josephine Bunch, Chelsea J. Nikula, Agata Mrowinska, Philip D Dunne, Rene Jackstadt, and Joshua D.G. Leach
- Subjects
0303 health sciences ,Mutation ,Mutant ,mTORC1 ,Biology ,medicine.disease_cause ,digestive system diseases ,Glutamine ,03 medical and health sciences ,0302 clinical medicine ,Cancer cell ,Genetics ,medicine ,Cancer research ,Amino acid transporter ,KRAS ,Signal transduction ,neoplasms ,030217 neurology & neurosurgery ,030304 developmental biology - 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.
- Published
- 2021