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.
None:
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.
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