LAUSR

Recent well-designed preclinical studies have demonstrated that KRAS mutations can activate the canonical NF-κB signaling pathway, which is a pivotal role in tumor progression. Therefore, inhibition of this KRAS-NF-κB axis would be a promising target to develop a new molecular targeted anticancer agent. Curcumin, a naturally occurring polyphenol derived from the plant Curcuma longa, has been shown to block NF-κB signaling pathway via at least two mechanisms; inhibition of IkB phosphorylation and inhibition of ubiquitin-dependent degradation of IκB. Recently dual-specificity tyrosine-regulated kinase (DYRK2), a positive regulator of the 26S proteasome, has been reported as a direct molecular target of curcumin, which is consisted with the inhibition of NF-κB signaling pathway by curcumin. Several preclinical studies have clearly demonstrated that curcumin exhibits anticancer effects in colorectal cancer model through NF-κB inhibition. However, since curcumin is highly lipophilic and orally administrated curcumin has very low bioavailability, its clinical application in cancer patients has been hampered. Very recently we developed a synthetic water-soluble prodrug CMG, curcumin mono-β-D-glucuronide, to overcome these problems. In this study, we investigated the anticancer effect of CMG on oxaliplatin (L-OHP) -resistant colorectal cancer cells HCT116 with KRAS mutation and p53 deletion (KRAS+p53- cells). Curcumin, the active substance released from CMG in vivo, showed similar effects regardless of KRAS/p53 mutation status in vitro. In xenograft models using KRAS+p53- HCT116 cells, intraperitoneal administration of CMG significantly superior antitumor effects compared to L-OHP monotherapy. Notably, no adverse events were noted in the CMG group, whereas bodyweight loss, severe myelosuppression, and liver damage were observed in the L-OHP group. Combination of CMG and L-OHP showed additive antitumor effects with moderate suppression of liver damage by L-OHP. These results indicate that CMG could be a novel anticancer drug with minimal toxicities for colon cancer patients with KRAS and p53 mutations. Citation Format: Hideaki Kakeya, Atsuhiro Kishimoto, Hitomi Umeta, Atsushi Imaizumi, Masashi Kanai. Development of an injectable water-soluble anticancer drug CMG for oxaliplatin-resistant colorectal cancer with KRAS mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C014. doi:10.1158/1535-7163.TARG-19-C014