A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer.

Abstract

Inhibitors of the oncogene KRAS hold promise for treating metastatic CRC (mCRC). Here we show that a selective, covalent small molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical CRC models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor-prognosis-associated Emp1⁺ transcriptional state to a WNT-driven Lgr5⁺ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of RAS(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5⁺ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.