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Updated: Jan 7, 2026

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

Yui Tanaka1,2, Mizuho Sakahara1, Hitomi Yamanaka1

  • 1Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

Nature Communications
|December 27, 2025
PubMed

Insights

KRAS-targeted therapies can cause colorectal cancer cells to boost ribosome production, making them vulnerable to RNA polymerase I inhibition. This finding offers new therapeutic strategies for KRAS-mutant colorectal cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • KRAS signaling pathway is crucial in colorectal cancer (CRC) development.
  • Current KRAS-targeted therapies show limited efficacy in CRC.
  • Drug resistance mechanisms in KRAS-mutant CRC require further investigation.

Purpose of the Study:

  • To investigate the cellular response to KRAS signaling inhibition in colorectal cancer.
  • To identify novel therapeutic targets for overcoming drug resistance in KRAS-mutant CRC.
  • To explore the role of ribosome biogenesis in KRAS inhibitor tolerance.

Main Methods:

  • Utilized KRAS signaling inhibitors (trametinib, AMG510) in KRAS-mutant CRC cell lines.
  • Analyzed gene expression profiles to assess ribosome biogenesis.
  • Evaluated the efficacy of RNA polymerase I inhibition in combination with KRAS inhibitors.
  • Tested therapeutic effects in preclinical models, including mouse models and patient-derived organoids (PDOs).

Main Results:

  • KRAS inhibition induced a cellular state with significantly enhanced ribosome biogenesis.
  • This KRAS-inhibitor-induced state exhibited vulnerability to RNA polymerase I inhibition.
  • Combination therapy with trametinib and RNA polymerase I inhibitor showed synergistic anti-tumor effects in preclinical models.
  • High ribosome biogenesis was identified as essential for maintaining the drug-tolerant state.

Conclusions:

  • Enhanced ribosome biogenesis is a key mechanism of drug tolerance to KRAS inhibition in CRC.
  • Targeting ribosome biogenesis presents a promising therapeutic strategy for KRAS-mutant CRC.
  • Combination therapies targeting KRAS signaling and ribosome biogenesis may improve treatment outcomes.

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