Ribosome biogenesis in embryo-like grand states as potential therapeutic target for KRAS mutant CRC

KRAS signaling is a promising target for cancer treatment, and the development of molecular targeted therapies has significantly improved the treatment outcome. However, cancer cells often adopt drug tolerant state to impede efficacy of chemotherapeutic agents. In colorectal cancer (CRC), therapeutic agents targeting KRAS have often failed to demonstrate a significant benefit, and the elucidation of its mechanism has been major clinical challenge. Here we show that MEK inhibitor, trametinib, and allele specific KRAS inhibitor, AMG510, induce the cellular state resembling the pluripotent naïve grand state of embryonic stem cells (ESCs). These cells are characterized by elevated ribosome biogenesis with Myc expression profile, yet global protein synthesis rate is low. We found they were vulnerable to the inhibition of ribosome biogenesis, and RNA polymerase I (RNA PolI) inhibition showed synergistic anti-tumor effects with trametinib and AMG510 in the autochthonous mouse model of intestinal tumors and in human patient-derived organoids with KRAS G12C mutation, respectively. These observations in PDOs demonstrated that CRC cells are equipotent to enter the pluripotent stem-like state by exploiting the cellular program of early embryogenesis and become tolerant to KRAS inhibition. High ribosome biogenesis is indispensable to maintain this cell state and is a potential therapeutic target of these cells. Our findings uncover previously unrecognized mechanisms of drug tolerance of CRC to KRAS inhibition, and provide the clue for the development of therapeutic strategies.