Antibody-drug conjugates: A new twist to overcome EGFR-TKIs resistance in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) accounts for 80-90 % of all lung cancer cases and is characterized by high incidence and mortality rates. The epidermal growth factor receptor (EGFR), one of the most frequently mutated genes in NSCLC, has become a key target for treatment through the development of EGFR-tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs have shown significant therapeutic effects, clinical observations indicate that most patients eventually develop drug resistance. Antibody-drug conjugates (ADCs) represent a potent strategy to overcome EGFR-TKIs resistance by precisely delivering cytotoxic payloads to tumor cells via targets such as EGFR itself or other relevant molecules. In this review, we provide a comprehensive overview of EGFR-TKIs, including their structure, clinical applications, and mechanisms of resistance. We examine the role of ADCs in EGFR-mutated NSCLC, focusing on current targets such as MET, HER2, TROP2, and EGFR, as well as emerging targets under investigation. It is worth mentioning that the development of bispecific ADCs represents a novel frontier in overcoming resistance. We also discuss other novel therapeutic approaches to overcome EGFR-TKIs resistance, including protein degradation-targeting chimeras, poly (ADP-ribose) polymerase inhibitors, aurora kinase inhibitors, and metabolic reprogramming strategies. Finally, we summarize the main challenges associated with ADCs-based therapies and highlight future directions for optimizing treatment in EGFR-TKI-resistant NSCLC.