ALK rearrangements and resistance mutations in non-small cell lung cancer: molecular mechanisms and therapeutic implications.

Anaplastic lymphoma kinase (ALK) gene rearrangements represent one of the well-characterized oncogenic drivers in non-small cell lung cancer (NSCLC), with the EML4-ALK fusion being the most common and clinically significant rearrangement. ALK inhibitors, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib has significantly improved clinical outcomes in ALK-rearranged NSCLC patients. However, the emergence of drug resistance remains inevitable which is mediated by either on-target mechanisms or off-target mechanisms. Mutations in the kinase domain, particularly in the solvent-front and gatekeeper regions alter the conformation of the ATP-binding site, leading to reduced binding affinity of ALK inhibitors. Importantly, G1202R-associated compound mutations confer high-level resistance, thereby limiting the effectiveness of currently available TKIs and posing a significant challenge in the clinical settings. In addition to acquired secondary mutations, the presence of the EML4-ALK variant 3 further worsens the prognosis and increases the risk of metastasis. Moreover, even when ALK is inhibited, activation of bypass signaling pathways can promote tumor progression via off-target mechanisms. To overcome these resistance mechanisms, the development of novel therapeutic strategies are required. By integrating structural biology, mutation evolution patterns, and emerging therapeutic approaches, this review underscores the need for next-generation inhibitors to overcome resistance and improve long-term outcomes in patients with ALK-positive NSCLC.