ALK阳性非小细胞肺癌靶向治疗耐药机制及治疗进展★

Mechanisms of resistance to targeted therapy and therapeutic advances in ALK-positive non-small cell lung cancer★

摘要:

间变性淋巴瘤激酶（ALK）基因融合突变是非小细胞肺癌（NSCLC）的一种独特分子亚型，占所有NSCLC病例的3%~7%。尽管ALK酪氨酸激酶抑制剂（TKI）如克唑替尼、阿来替尼及洛拉替尼等显著改善了患者的预后，但耐药问题始终是临床治疗中的主要挑战。ALK-TKIs原发性耐药涉及罕见ALK融合变异体、ALK点突变、合并其他驱动基因突变及肿瘤微环境异常等因素；继发性耐药则分为ALK依赖性耐药和ALK非依赖性耐药，前者主要通过激酶域突变、基因扩增等机制产生，后者则涉及旁路信号激活、组织学表型转化（如向小细胞肺癌转化）等途径。为应对耐药挑战，新一代ALK-TKIs（如四代TPX-0131、NVL-655等）及联合治疗策略（如免疫治疗、抗血管生成治疗、化疗等）为患者提供了更多临床治疗选择。未来，进一步优化药物选择策略、整合耐药突变检测技术及制定个体化联合治疗方案，将是推动ALK阳性NSCLC精准治疗进展的关键方向。

Abstract:

Anaplastic lymphoma kinase (ALK) gene fusion mutation is a unique subtype of non-small cell lung cancer (NSCLC), accounting for 3%-7% of all NSCLC cases. Although ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib, and lorlatinib have significantly improved the prognosis of patients, acquired resistance remains a major clinical challenge. Primary resistance to ALK-TKIs involves rare ALK fusion variants, ALK point mutations, coexisting driver gene mutations, and abnormal tumor microenvironments. Secondary resistance can be divided into ALK-dependent and ALK-independent resistance. The former is mainly produced by kinase domain mutation, ALK amplification and other mechanisms, while the latter involves bypass signal activation and histological phenotype transformation (such as transformation to small cell lung cancer). To address the challenge of drug resistance, new-generation ALK-TKIs (such as fourth-generation TPX-0131 and NVL-655) and combination therapies (such as immunotherapy, anti-angiogenic therapy, and chemotherapy) have emerged as promising therapeutic options. Future advancements in ALK-positive NSCLC management will rely on optimizing drug selection and sequencing strategies, integrating resistance mutation profiling, and developing personalized combination regimens to achieve precision oncology goals.