Five-Gene Expression Signature Associated With Acquired FOLFIRI Resistance and Survival in Metastatic Colorectal Cancer

FOLFIRI, a combination of folinic acid, 5-fluorouracil, and irinotecan, is one of the recommended first- line chemotherapeutic treatments for metastatic colorectal cancer. Unfortunately, acquired FOLFIRI resistance represents a common obstacle in the treatment of metastatic colorectal cancer patients. Thus, we aimed to identify mechanisms, gene alterations, and gene expression signatures contributing to acquired FOLFIRI resistance by mimicking this problem in a cell culture model and subsequent translation in clinical data sets. Three FOLFIRI-resistant colorectal cancer (CRC) cell lines were established by continuous FOLFIRI treatment. Comparative mutation screening (161 genes) and transcriptomics (pathway and differential expression analyses) were performed in parental and resistant cells. Data reconciliation was performed in GSE62322, a clinical FOLFIRI responder data set (intrinsic resistance). Relapse-free survival (RFS) associations of identified differentially expressed genes and potential gene signatures were investigated in 8 clinical CRC data sets. No mutual genetic alterations were found in FOLFIRI-resistant derivatives. Resistant cell lines displayed activation of mitogen-activated protein kinase, immune response, and epithelial-mesenchymal transition pathways. Twelve differentially expressed genes, significantly differentially expressed in at least 2 of the 3 resistant cell lines, were identified. Comparison with GSE62322 and subsequent survival analyses revealed a 5-gene FOLFIRI signature comprised of CAV2, TNC, TACSTD2, SERPINE2, and PERP that was associated with RFS in multiple data sets including the cancer genome atlas CRC (hazard ratio [HR] =2.634, P = 4.53 x 10-6), in pooled samples of all data sets (all stages [N = 1981]: HR = 1.852, P = 6.44 x 10-13; stage IV [N = 260]: HR = 2.462, P = 5.22 x 10-9). A multivariate Cox regression analysis identified the 5-gene signature as an independent prognostic factor in the cancer genome atlas data set (HR = 1.89, P = .0202). Our analyses revealed a 5-gene FOLFIRI resistance signature associated with RFS that may help predict FOLFIRI resistance and thus avoid unnecessary ineffective treatment. Signature members might also represent targets to fight FOLFIRI resistance. (c) 2025 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).