Therapeutic targeting of SLC6A8 creatine transporter inhibits KRAS mutant and wildtype colon cancer and modulates human creatine levels

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.; Spector, S.; Raza, S.; Tavazoie, M. F.; Tavazoie, S. F.

doi:10.1101/2021.04.26.441371

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bioRxiv · 10.1101/2021.04.26.441371

Therapeutic targeting of SLC6A8 creatine transporter inhibits KRAS mutant and wildtype colon cancer and modulates human creatine levels

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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 creatine transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels and induces tumor cell apoptosis in CRC. RGX-202 suppressed tumor growth across KRAS wild-type and KRAS mutant xenograft, syngeneic and patient-derived xenograft colorectal cancers. Anti-tumor 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 metastatic CRC patients enrolled in a Phase-1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of pre-clinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, revealing a critical target for CRC.

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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., Spector, S., Raza, S., Tavazoie, M. F., Tavazoie, S. F.. 2021-04-26. Therapeutic targeting of SLC6A8 creatine transporter inhibits KRAS mutant and wildtype colon cancer and modulates human creatine levels. https://doi.org/10.1101/2021.04.26.441371

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