Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels Journal Article

   

Authors:	Kurth, I.; Yamaguchi, N.; Andreu-Agullo, C.; Tian, H. S.; Sridhar, S.; Takeda, S.; Gonsalves, F. C.; Loo, J. M.; Barlas, A.; Manova-Todorova, K.; Busby, R.; Bendell, J. C.; Strauss, J.; Fakih, M.; McRee, A. J.; Hendifar, A. E.; Rosen, L. S.; Cercek, A.; Wasserman, R.; Szarek, M.; Spector, S. L.; Raza, S.; Tavazoie, M. F.; Tavazoie, S. F.
Article Title:	Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels
Abstract:	Colorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor apoptosis. RGX-202 suppressed CRC growth across KRAS wild-type and KRAS mutant xenograft, syngeneic, and patient-derived xenograft (PDX) tumors. Antitumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5-fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of preclinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, thus revealing a critical therapeutic target. Copyright © 2021 The Authors, some rights reserved;
Keywords:	cancer growth; metabolism; cell death; pharmacodynamics; cancer mortality; tumors; colon cancer; wild types; mammals; in-vitro; diseases; small molecules; vitro and in vivo; cancer progression; anti-tumor efficacy; atp level
Journal Title:	Science Advances
Volume:	7
Issue:	41
ISSN:	2375-2548
Publisher:	Amer Assoc Advancement Science
Date Published:	2021-10-08
Start Page:	eabi7511
Language:	English
DOI:	10.1126/sciadv.abi7511
PROVIDER:	scopus
PMCID:	PMC8494442
PUBMED:	34613776
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85116788713&doi=10.1126%2fsciadv.abi7511&partnerID=40&md5=be64060559765a99c3a2fe2b52b18927
Notes:	Article -- Export Date: 2 November 2021 -- Source: Scopus

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