Transcriptomic Landscape of Paclitaxel-Induced Multidrug Resistance in 3D Cultures of Colon Cancer Cell Line DLD1

Multidrug resistance (MDR) significantly contributes to colon cancer recurrence, making it essential to understand its molecular basis for improved therapies. This study aimed to identify genes and pathways involved in resistance to standard chemotherapeutics by comparing transcriptome profiles of sensitive and paclitaxel-induced MDR colonospheres. Cell viability and growth were assessed following treatment with 5-fluorouracil, oxaliplatin, irinotecan, bevacizumab, and cetuximab. Drug concentrations in culture media posttreatment were measured using high-performance liquid chromatography (HPLC). RNA sequencing (RNA-seq) of untreated sensitive and resistant colonospheres identified differentially expressed genes linked to baseline resistance. Our results confirmed cross-resistance in the resistant model, showing highest oxaliplatin tolerance may involve mechanisms beyond efflux. Transcriptome analysis highlighted upregulation of PIGR and activation of the ribosomal signaling pathway as potential resistance mediators. Notably, AKR1B10, a gene linked to chemotherapeutic detoxification, was overexpressed, whereas genes related to adhesion and membrane transport were downregulated. The overexpression of ribosomal protein genes suggests ribosome biogenesis plays a key role in acquired resistance. These findings suggest that targeting ribosome biogenesis and specific deregulated genes such as PIGR and AKR1B10 may offer promising strategies to overcome MDR in colon cancer.