CDK12 deficiency is vulnerable to mTOR inhibition in colorectal cancer by remodeling of translatome

In this study, we leveraged AI algorithms and database screening to identify a synthetic lethal interaction between CDK12 and mTOR in CRC. We demonstrated that cotreatment with a CDK12 degrader and an mTOR inhibitor exhibits a synergistic antitumor effect in CRC cell lines both in vitro and in vivo. Mechanistically, this synergistic regimen involves remodeling of the translatome through CDK12 kinase-independent regulation of rRNA modification and ribosome biogenesis, along with mTOR mediated protein translation. Furthermore, we validated the feasibility of this combined therapeutic strategy in clinical samples from CRC patients, providing a foundation for future clinical research. Among them, RNA seq and RNC seq were performed to verify the mechanism of this study.