2025年新着論文 58　細胞情報学分野から論文が発表されました

Ribosome biogenesis as a potential therapeutic target in KRAS mutant colorectal cancer

Nat Commun. 2025 Dec 27. doi: 10.1038/s41467-025-67979-9. Online ahead of print.

Authors

Yui Tanaka^#^1 2, Mizuho Sakahara^#¹, Hitomi Yamanaka¹, Yasuko Natsume¹, Daisuke Kusama¹, Kohei Kumegawa³, Harunori Yoshikawa⁴, Yuich Abe^5 6, Koji Okabayashi², Shimpei Matui², Yuko Kitagawa², Naohiko Koshikawa⁷, Hiroki Osumi⁸, Eiji Shinozaki⁸, Satoshi Nagayama⁹, Jun Adachi⁵, Reo Maruyama^3 10, Ryoji Yao¹¹

Affiliations

¹ Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
² Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
³ Cancer Cell Diversity Project, NEXT-Ganken Program, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁴ Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
⁵ Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
⁶ Immunoproteomics Laboratory, Institute for Glyco-core Research (iGCORE), Gifu University, Gifu, Japan.
⁷ Department of Life Science and Technology, Institute of Science Tokyo, Yokohama, Japan.
⁸ Department of Gastrointestinal Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁹ Department of Surgery, Uji-Tokushukai Medical Center, Uji, Japan.
¹⁰ Project for Cancer Epigenomics, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
¹¹ Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. ryao@jfcr.or.jp.

^# Contributed equally.

PMID: 41455700
DOI: 10.1038/s41467-025-67979-9

Abstract

Molecular targeted therapies targeting KRAS signaling have significantly improved patient outcomes, but they have not achieved sufficient therapeutic efficacy in colorectal cancer (CRC). Here, we demonstrate that a subset of KRAS-mutant CRC cells transitions to a cellular state characterized by enhanced ribosome biogenesis upon KRAS signaling inhibition. The mitogen-activated protein kinase kinase inhibitor, trametinib, and AMG510 induce a cellular state characterized by a gene expression profile highly enriched for ribosome biogenesis. We find that they are vulnerable to the inhibition of RNA polymerase I, and they exhibit synergistic anti-tumor effects with trametinib in an autochthonous mouse model of intestinal tumors and human patient-derived organoids (PDOs). These observations demonstrate that high ribosome biogenesis induced by KRAS inhibition is indispensable to maintain this cellular state and is a potential therapeutic target. Overall, this study reveals novel mechanisms of drug tolerance to KRAS inhibition, thereby facilitating the development of new therapeutic strategies.

Conflict of interest statement

Competing interests: The authors declare no competing interests.

102 references

カテゴリー: ニュース