MECHANISMS OF DRUG-RESISTANT CANCER CELLS: ROLE OF CHEMORESISTANCE MEDIATED BY CELLULAR EFFLUX PUMPS AND TARGET MUTATIONS

Abstract

Chemoresistance is a potent barrier in effective cancer treatment due to various cellular and molecular processes that lower the efficacy of drugs. In this study, the contribution of cellular efflux pumps, genetic mutations, DNA repair pathways, and the tumor microenvironment in drug resistance mediation is explored. Using in vitro assays, CRISPR-Cas9 gene editing, and molecular analytical methods, the study detected significant resistance mechanisms in chemoresistant breast (MCF-7R), lung (A549R), and colorectal (HCT116R) cancer cell lines. Findings confirmed enhanced expression of MDR1, MRP1, and BCRP efflux transporters, which actively decreased intracellular drug levels. Western blot analysis validated higher levels of MGMT and ERCC1, reflecting improved DNA repair capabilities. In addition, the co-culture system demonstrated that tumor microenvironment-induced fibroblast interactions and hypoxia conditions highly increased levels of HIF-1α, which augments resistance. CRISPR-Cas9 knockout of MDR1 and ERCC1 using CRISPR-Cas9 restored drug sensitivity and improved apoptotic responses. The findings emphasize the need for conjugated therapies involving efflux pumps, DNA repair mechanisms, and tumor microenvironment targets to effectively deliver cancer therapy. The next area of study would be incorporating nanotechnology-derived delivery systems with targeted treatment planning to deliver optimum therapeutic effects against drug-resistant malignancies.