Abstract ABSTRACT BACKGROUND: Chemoresistance remains a major challenge to long-term survival in colorectal cancer (CRC). Although lipid metabolic reprogramming is a key adaptation under sustained drug pressure, its dynamic changes and core regulators remain unclear. Defining the clonal evolution and metabolic drivers of acquired resistance is essential for identifying therapeutic targets. METHODS: Forty-six CRC PDOs were established and subjected to long-term, dose-escalating FOLFOX induction to generate resistance models. Whole-exome sequencing (WES) and RNA-seq were performed before and after induction to assess genomic stability, clonal evolution, and transcriptional remodeling. Multi-cohort validation used TCGA, ICGC-ARGO, and recurrent tumor samples from our institution. Functional assays—including lipid metabolic activity, stemness phenotype, and chemosensitivity analyses—were performed for candidate genes, followed by overexpression and knockdown PDO models to evaluate in vivo effects using xenografts. RESULTS: Resistant PDOs exhibited denser and more irregular structures with reduced gland-like morphology. Early-stage PDOs retained ∼80% of the mutational landscape of primary tumors; with prolonged induction, drug pressure drove clonal selection and genomic drift, with ∼60% of mutations retained in late stages, indicating PDOs maintain tumor representativeness during long-term culture. Copy-number alterations of dominant clones correlated with gene expression, suggesting a gene-dosage effect. Multi-omics analyses revealed marked upregulation of CIDEA in resistant PDOs, accompanied by lipid metabolic remodeling and increased expression of FASN, ACACB, FABP1, CD36, along with activation of MAPK and PI3K-Akt pathways. Across TCGA, ICGC-ARGO, and recurrent cohorts, high CIDEA expression was associated with advanced stage and higher recurrence. Functionally, CIDEA overexpression promoted lipid droplet accumulation and enhanced fatty acid oxidation (FAO), driving chemoresistance, whereas CIDEA knockdown reduced FAO, downregulated lipid metabolic genes, and restored chemosensitivity. FAO inhibition reversed resistance in CIDEA-overexpressing cells. In vivo xenografts confirmed that CIDEA knockdown improved chemosensitivity, while CIDEA-driven resistance was reversed by FAO inhibition. CONCLUSIONS: This study delineates the clonal evolution and lipid metabolic remodeling underlying acquired chemoresistance in CRC and identifies CIDEA as a key driver that promotes resistance through lipid droplet accumulation and enhanced FAO, highlighting its therapeutic potential. Key words: Colorectal cancer; Chemoresistance; Patient-derived organoids; Clonal evolution; Lipid metabolic reprogramming: Citation Format: Haigui Wan, Yao Shang, Dongwen Chen, Chuling Hu, Yiran Bie, Zhengran Zhou, Zhengyu Wei, Chong Chen, Yifan Zheng, Peishan Hu, Xiaojian Wu. Drug pressure driven evolution upregulates CIDEA to reprogram lipid metabolism and promote chemoresistance in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3530.
Wan et al. (Fri,) studied this question.