Abstract
Targeted therapy has markedly improved outcomes for patients with non‑small cell lung cancer (NSCLC). However, the emergence of drug resistance remains a major clinical challenge, limiting long‑term treatment efficacy. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, a revolutionary gene‑editing technology, offers precise and efficient genetic modifications, providing new insights into the mechanisms of drug resistance in NSCLC. The present review explored the application of CRISPR/Cas9 in overcoming resistance associated with key oncogenic drivers, including EGFR, KRAS, ALK, ROS1, MET and BRAF. It summarized recent advances in CRISPR‑based strategies to reverse resistance, enhance targeted therapy effectiveness and develop potential therapeutic interventions. Additionally, it discussed current limitations, including off‑target effects, delivery challenges and ethical concerns, while highlighting future directions for clinical translation. Using CRISPR/Cas9 technology may pave the way for novel, personalized treatment approaches in NSCLC, ultimately improving patient outcome.