Modelling oxaliplatin resistance in colorectal cancer reveals a SERPINE1 -based gene signature (RESIST-M) and therapeutic strategies for pro-metastatic CMS4 subtype

Drug resistance and distant metastases are major contributors to mortality in colorectal cancer (CRC). Here we investigate mechanisms underlying acquired resistance to oxaliplatin, a first-line, standard-of-care CRC treatment. We generated oxaliplatin-resistant CRC tumor cells with clinically relevant dosing regimen, which displayed enhanced metastatic potential. Transcriptomic and phenotypic analyses revealed a critical function for cholesterol biogenesis in modulating TGF-β signaling activity, which in turn regulates SERPINE1 expression, a gene we identified as a key player in promoting drug resistance and metastasis. Additionally, we uncovered a SERPINE1 -associated nine-gene expression signature, RESIST-M, that can predict overall and relapse-free survival (RFS) in clinical cohorts and is able to stratify patients into CMS4/iCMS3-fibrotic CRC-subtypes, underscoring its clinical utility. Using mouse tumor models, we provide further evidence that targeting SERPINE1 and cholesterol biogenesis can be viable approaches to re-sensitize the resistant pro-metastatic CRC cells to oxaliplatin. This study not only elucidates the molecular underpinnings of drug resistance and metastasis in primary CRC, but also offers prognostic and therapeutic strategies to guide clinical management of the disease.