ALK-Targeted Therapy: Resistance Mechanisms and Emerging Precision Strategies

Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, plays a central oncogenic role in the initiation and progression of diverse malignancies. Aberrant ALK activation generally results from structural alterations or dysregulated expression, leading to persistent activation of downstream signaling pathways that drive tumor cell proliferation, survival, and metastasis. ALK gene abnormalities predominantly encompass fusions, point mutations, and amplifications, with EML4-ALK-positive non–small cell lung cancer representing a canonical example. The advent of ALK-targeted inhibitors has constituted a major therapeutic milestone for ALK-positive tumors. From first-generation Crizotinib to third-generation Lorlatinib, successive agents have been refined for target selectivity, central nervous system penetration, and coverage of resistance-associated mutations, substantially improving patient survival and intracranial disease control. Nonetheless, the emergence of acquired resistance remains an overarching challenge, mediated by secondary kinase domain mutations, activation of bypass signaling pathways, and tumor phenotypic transformation. This review presents an integrative synthesis of ALK-targeted therapeutic developments, elucidates underlying resistance mechanisms, and surveys emerging strategies, providing a comprehensive perspective on current advances and future directions in precision management of ALK-driven malignancies.