ALK-based dual inhibitors: Focus on recent development for non-small cell lung cancer therapy

Abstract

As a prevalent oncogenic driver gene in non-small cell lung cancer (NSCLC), ALK represents a crucial and efficacious therapeutic target. To date, seven ALK inhibitors have been approved for ALK fusion-positive NSCLC, with several others undergoing clinical trials. These therapies demonstrate significant efficacy in ALK fusion-positive NSCLC patients. However, acquired resistance mechanisms, including ALK kinase domain mutations, ALK gene amplification, and bypass pathway activation, significantly compromise the efficacy of targeted therapy in ALK fusion-positive NSCLC. Therefore, the discovery of novel ALK inhibitors and the development of related treatment strategies remain critical. Compared to the combination therapy strategy based on ALK inhibitors, dual-target inhibitors (targeting two distinct pathways within a single molecule) may reduce systemic toxicity and mitigate resistance mechanisms in cancer treatment. Notably, recent years have witnessed remarkable progress in dual-target ALK inhibitor development for NSCLC. Consequently, this review aims to summarize the advancements achieved through dual ALK-based inhibitors in NSCLC therapy, analyze their rational design and structure-activity relationships, and provide perspectives for overcoming resistance through next-generation inhibitors and innovative therapeutic approaches.