Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels
Kurth I, Yamaguchi N, Andreu-Agullo C, Tian HS, Sridhar S, Takeda S, Gonsalves FC, Loo JM, Barlas A, Manova-Todorova K, Busby R, Bendell JC, Strauss J, Fakih M, McRee AJ, Hendifar AE, Rosen LS, Cercek A, Wasserman R, Szarek M, Spector SL, Raza S, Tavazoie MF, Tavazoie SF
Science advances · 73 citations
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Independent funding
- Government
- National Cancer Institute
- Government
- National Center for Advancing Translational Sciences
- Government
- NCATS NIH HHS
- Government
- NCI NIH HHS
- Grants
- National Center for Advancing Translational Sciences (# UL1 TR001866); National Cancer Institute (#P30-CA008748)
Based on 4 listed funder(s).
Publication
- Published
- 2021-10-08 · Sci Adv · vol. 7 · issue 41 · p. eabi7511
- Publisher
- American Association for the Advancement of Science
- Cited
- 92 citations · more than 95% of similar papers · 3.4× the field average
- Impact
- Top 10% most cited in its field
- References
- 33 works
- Access
- Open access (journal) · CC-BY-NC
- Research areas
- Cancer, Hypoxia, and Metabolism · Muscle metabolism and nutrition · Biochemical and Molecular Research
- Keywords
- Creatine, Transporter, Colorectal cancer, Solute carrier family, Cancer, Medicine, Internal medicine, Endocrinology, Cancer research, Biology, Biochemistry, Gene
- MeSH
- cell line, tumor, animals, humans, mice, mice, nude, colorectal neoplasms, colonic neoplasms, creatine, membrane transport proteins, nerve tissue proteins, antineoplastic agents, cell proliferation, mutation, proto-oncogene proteins p21(ras), plasma membrane neurotransmitter transport proteins
24 authors
From US, SG
- Isabel Kurth · corresponding
- Norihiro Yamaguchi · correspondingRockefeller University
- Celia Andreu-Agulló · corresponding
- Helen S. TianRockefeller University
- Subhasree Sridhar
- Shugaku Takeda
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC).
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