Small Interfering RNA Strategies to Overcome Drug Resistance in Cancer: Pathway Targeting and Translational Advances

The emergence of therapeutic resistance remains the primary challenge to achieving durable responses in cancer treatment, thereby limiting the long-term e"cacy of several chemotherapies and targeted agents. Resistance may develop through diverse and often overlapping mechanisms. Conventional approaches to overcome resistance, such as dose escalation or combination regimens, are frequently constrained by systemic toxicity and adaptive tumor evolution. Moreover, many central drivers of resistance, including transcription factors and non-enzymatic regulatory proteins, remain inaccessible to therapeutics. Small interfering RNAs (siRNAs) o#er a fundamentally distinct and pathway-centric approach to overcoming drug resistance by enabling sequence-specific degradation of resistance-associated messenger RNAs. By acting upstream of protein synthesis, siRNA therapeutics can directly suppress both druggable and traditionally undruggable targets, including e$ux transporters, anti-apoptotic regulators, DNA repair enzymes, epigenetic modifiers, epithelial-mesenchymal transition transcription factors, and key oncogenic drivers such as KRAS and MYC. Advances in chemical modification and delivery platforms have significantly improved siRNA stability, specificity, and pharmacokinetic durability, enabling sustained gene silencing in vivo. The current review examines the molecular principles of siRNA-induced gene silencing and evaluates the current siRNA-based strategies targeting key mechanisms of chemotherapy resistance. Preclinical and translational studies demonstrating the reversal of multidrug resistance, restoration of apoptotic sensitivity, disruption of DNA repair-mediated tolerance, and suppression of adaptive oncogenic signaling are highlighted. In addition, the emerging clinical trials that validate siRNA-based approaches in cancer treatment are summerized. Cite this article as: Bardaweel SK, Hajjo R, Sabbah DA, Qasem DA. Small interfering RNA strategies to overcome drug resistance in cancer: pathway targeting and translational advances. Eurasian J Med. 2026, 58(1), 1350, doi:10.5152/eurasianjmed.2026.251350.