Genetic and microenvironmental evolution of colorectal liver metastases under chemotherapy

Drug resistance limits the efficacy of chemotherapy for colorectal cancer liver metastasis (CRLM). However, the evolution of CRLM during drug treatment remains poorly elucidated. Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level. By decoupling intrinsic and acquired resistance, we find that hepatocyte and myeloid cell infiltration contribute to 38.5% and 23.1% of acquired resistance, respectively. Importantly, SMAD4 mutations and chr20q copy-number gain are associated with intrinsic chemoresistance. Gene interference experiments suggest that SMAD4R361H/C mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4R361H/C cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance. [Display omitted] •Longitudinal sequencing reveals TME reorganization after BVZ-C therapy•Acquired resistance associates with the spatial distance of tumors and hepatocytes•SMAD4 mutation and chr20q copy-number gain associate with intrinsic resistance•STAT3 inhibition overcomes resistance in SMAD4-mutant cells and holds therapeutic potential Shi et al. identified spatial and genetic factors contributing to intrinsic and acquired resistance in patients with colorectal cancer liver metastases. By demonstrating the restoration of therapeutic response with a STAT3 inhibitor, this study paves the way for targeted therapeutic strategies to overcome drug resistance.