News Releases & Research Results Development of chemically - modified microRNA143-3p targeting RAS networks -

RAS mutation is frequently observed in various kinds of cancers. However, the RAS-targeting anticancer drug has not been developed yet, because of tiny pockets in the protein structure and alternative pathways leading to RAS-positive circuit. The aberrant activation of PI3K/AKT and MAPK/ERK signaling pathways of RAS-effector pathways is often seen in many kinds of cancers, and many therapeutic agents targeting molecules related to these pathways have been developed. The regulation of these pathways is a very important strategy for treating RAS-mutant cancers. In fact, numerous inhibitors targeting these pathways have been clinically evaluated. For instance, for the MAPK pathway, the inhibitors for RAF, MEK and ERK have been clinically evaluated, as well as the inhibitors for the PI3K/AKT pathway. However, the challenge of suppressing RAS-driven cancers remains. Global suppression of these signaling pathways is crucial for a durable effect on cancers, because inhibition of only a single pathway will result in resistance to the agent through activation of alternative signaling pathways. For these reasons, another strategy to attack RAS-driven cancers is necessary. In the view of cellular localization of RAS protein, development of antibody medicine is fairly difficult. One potential approach is to downregulate KRAS expression with small interfering RNA or miRNA.

In such a situation, we developed more than 100 different MIR143 derivatives for two main reasons. The first reason is to make MIR143 RNase resistant. The other reason is to enhance the ability to bind the target genes of MIR143 and the ability to suppress the translation of those genes. Among the derivatives, a chemically-modified MIR143-3p (CM-MIR143-3p), which is chemically modified only in the passenger strand, showed strikingly potent anti–proliferative activity with good RNase resistance. The CM-MIR143-3p systemically inhibits the KRAS signaling networks, which include RAS-MAPK and PI3K-AKT effector signaling pathways, by silencing KRAS, SOS1, AKT and ERK both in vitro and in vivo in colon cancer cells (1., Akao et al., 2018). In the same study, we further demonstrated the synergistic effect of an EGFR inhibitor and CM-MIR143-3p in KRAS mutant cells. Other than colorectal cancer, CM-MIR143-3p displayed tumor suppressor effects on various types of cancers. Our group found that CM-MIR143-3p exerts efficient suppression of KRAS networks in KRAS-mutant bladder cancer (2., Yoshikawa et al., 2019), gastric cancer (3., Tokumaru et al., 2019), and renal cell cancer (4., Takai et al., 2019) by systematically suppressing not only KRAS but also PI3K/AKT and MAPK/ ERK pathways. In this time, we reported that CM-MIR143-3p efficiently inhibits cell growth of rhabdomyosarcoma cells by suppressing KRAS/FAX3-FOXO1 cascade (5., Sugito et al., 2020).

Our CM-MIR143-3p has enabled us to understand the detailed signaling networks of KRAS and related signaling cascades. Given the critical effects of CM-MIR143-3p in suppressing the expression of both RAS and its effector signaling genes, we expect that CM-MIR143-3p will efficiently function as a therapeutic agent to impair the KRAS signaling networks in clinical study.

Colon cancer

Impairment of K-Ras signaling networks and increased efficacy of epidermal growth factor receptor inhibitors by a novel synthetic miR-143. Akao Y, Kumazaki M, Shinohara H, Sugito N, Kuranaga Y, Tsujino T, Yoshikawa Y, Kitade Y. Cancer Sci. 2018 May;109(5):1455-1467. doi: 10.1111/cas.13559. Epub 2018 Apr 14.

Bladder cancer

Anti-cancer Effects of a Chemically Modified miR-143on Bladder Cancer by Either Systemic or Intravesical Treatment. Yoshikawa Y, Taniguchi K, Tsujino T, Heishima K, Inamoto T, Takai T, Minami K, Azuma H, Miyata K, Hayashi K, Kataoka K, Akao Y. Mol Ther Methods Clin Dev. 2019 Feb 20;13:290-302. doi: 10.1016/j.omtm.2019.02.005. eCollection 2019 Jun 14.

Gastric cancer

Synthetic miR-143Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase. Tokumaru Y, Tajirika T, Sugito N, Kuranaga Y, Shinohara H, Tsujino T, Matsuhashi N, Futamura M,Akao Y, Yoshida K. Int J Mol Sci. 2019 Apr 5;20(7):1697. doi: 10.3390/ijms20071697.

Kidney cancer

Synthetic miR-143Exhibited an Anti-Cancer Effect via the Downregulation of K-RAS Networks of Renal Cell Cancer Cells In Vitro and In Vivo. Takai T, Tsujino T, Yoshikawa Y, Inamoto T, Sugito N, Kuranaga Y, Heishima K, Soga T, Hayashi K, Miyata K, Kataoka K, Azuma H, Akao Y. Mol Ther. 2019 May 8;27(5):1017-1027. doi: 10.1016/j.ymthe.2019.03.004. Epub 2019 Mar 13.

Soft tissue tumor

Synthetic MIR143-3p suppresses cell growth in rhabdomyosarcoma cells by interrupting RAS pathways including PAX3-FOXO1. Sugito N, Heishima K, Ito Y, Akao Y.

Research Contact

Professor Yukihiro Akao
The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University
Yanagido 1-1, Gifu City, 501-1194, Japan
Tel: 058-326-7607
Email: yakao"at"gifu-u.ac.jp

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Email: kohositu"at"gifu-u.ac.jp

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