New advances in understanding the mechanisms and treatment challenges of ALK-targeted therapy resistance in lung cancer.

Despite the development of various effective anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), therapeutic resistance remains a major challenge. Both on-target and off-target mechanisms have been identified as key contributors to resistance. With the popularization of genetic testing and the development of precision therapies, the prognosis and survival of patients with ALK-positive non-small cell lung cancer (NSCLC) have improved. However, even with second- and third-generation ALK-TKIs, overcoming resistance remains difficult. Resistance frequently arises during approved treatments, underscoring the need for further research to elucidate the molecular events and resistance mechanisms associated with ALK-positive lung cancer. The discovery of anaplastic lymphoma kinase (ALK) rearrangement as an actionable oncogenic driver in NSCLC has established a biomarker-driven treatment paradigm for advanced disease. This article summarizes current knowledge of the mechanisms of resistance to ALK-targeted therapy in lung cancer, including both primary and acquired mechanisms, treatment strategies following resistance, recent therapeutic advances, and the impact of the immune system and tumor microenvironment. A deeper understanding of ALK-targeted therapy resistance is critical for developing new treatment strategies and may provide important insights to guide the diagnosis, treatment, and management of patients with resistant ALK⁺ lung cancer.