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

## TL;DR

KRAS-mutant colorectal cancer cells become dependent on ribosome biogenesis when treated, making RNA polymerase I inhibition a potential new therapy.

## Contribution

KRAS inhibition induces a new cellular state with increased ribosome biogenesis, which can be targeted for treatment.

## Key findings

- KRAS inhibition leads to enhanced ribosome biogenesis in CRC cells.
- Inhibiting RNA polymerase I synergizes with trametinib to reduce tumor growth.
- This cellular state is vulnerable to RNA polymerase I inhibition in mouse models and organoids.

## 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.

Drug tolerance to KRAS inhibition remains a major challenge in cancer therapy. Here the authors find that KRAS inhibition induces a cellular state characterized by enhanced ribosome biogenesis in KRAS-mutant colorectal cancer cells and these cells are vulnerable to inhibition of RNA polymerase I.