Overcoming EGFR mutation resistance: Dual inhibition strategies using TKIs in non-small cell lung cancer therapy

Epidermal Growth Factor Receptor (EGFR) is a critical target in the development of novel anticancer therapies, particularly for non-small cell lung cancer (NSCLC). Currently, third-generation EGFR inhibitors, such as osimertinib, are at the forefront of clinical treatment for EGFR-mutant NSCLC. However, their therapeutic efficacy has been significantly compromised by the emergence of drug resistance, driven by EGFR mutations and alternative oncogenic pathways. Given the complex interplay between EGFR and other oncogenic pathways, including MET, HER2, VEGFR-2, and PI3K, dual-target inhibitors have emerged as a promising strategy to overcome the limitations of existing therapies by simultaneously targeting multiple pathways involved in tumour growth and survival. The development of dual-target EGFR inhibitors offers several advantages, including improved therapeutic efficacy, reduced dosage requirements, lower toxicity, and a decreased likelihood of resistance development. In this review, we emphasize the rational selection of target combinations and explore key scaffold designs, examining how specific chemical structures influence their biological activity as dual-target inhibitors. The advancement of dual-target inhibitors represents a transformative approach to NSCLC treatment, offering a more effective and durable solution to combat drug resistance and improve clinical outcomes.