Ribosome biogenesis as a potential therapeutic target in KRAS mutant colorectal cancer
- Yui Tanaka
- Mizuho Sakahara
- Hitomi Yamanaka
- Yasuko Natsume
- Daisuke Kusama
- Kohei Kumegawa
- Harunori Yoshikawa
- Yuich Abe
- Koji Okabayashi
- Shimpei Matui
- Yuko Kitagawa
- Naohiko Koshikawa
- Hiroki Osumi
- Eiji Shinozaki
- Satoshi Nagayama
- Jun Adachi
- Reo Maruyama
- Ryoji Yao
2025-12-27
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.