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

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. ### Competing Interest Statement MFT and SFT are co-founders and shareholders of Rgenix and members of its scientific advisory board. MFT, IK, FCG, CAA, ST, SS, FG, RB, RW, RW and SR are shareholders of Rgenix. MFT, IK, FCG, CAA, ST, FG, RW and SR are current and SS past employees of Rgenix. All other authors declare that they have no competing interests.