Strategies for overcoming ABC transporter mediated drug resistance in colorectal cancer

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with multidrug resistance (MDR) significantly limiting the effectiveness of chemotherapy. A major contributor to MDR is the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (ABCB1/P-gp), breast cancer resistance protein (ABCG2/BCRP), and multidrug resistance-associated proteins (ABCC/MRPs). These transporters actively efflux chemotherapeutic agents, reducing their intracellular drug accumulation and efficacy. This review outlines both clinical and emerging strategies that aim to overcome ABC transporter-mediated resistance in CRC. Herein, we detail the functional role of ABC transporters in CRC, followed by clinically tested approaches, such as pharmacological inhibitors, natural compound inhibitors, as well as nanoparticle-based drug delivery systems, that have been explored to circumvent resistance. In addition, we discuss emerging preclinical approaches, including CRISPR/Cas9 gene-editing, RNA interference, epigenetic modulators, and gut microbiome-targeted interventions, that hold promise for future therapeutic translation. By integrating clinically validated and experimental strategies, this review highlights the importance of a multimodal approach to effectively circumvent MDR in CRC and optimize personalized treatment strategies to improve clinical outcomes.