胃肠间质瘤靶向治疗耐药的分子机制及治疗策略

Molecular mechanism and therapeutic strategy for resistance to tyrosine kinase inhibitors in targeted treatment of gastrointestinal stromal tumors

胃肠间质瘤（GIST）是胃肠道最常见的间叶源性肿瘤。功能获得性突变所致的c-kit或PDGFRA受体酪氨酸激酶异常活化是大多数GIST发病的关键因素。伊马替尼及舒尼替尼等分子靶向药物可特异性抑制酪氨酸激酶受体活化．其作为治疗晚期GIST及高危GIST术后辅助治疗的一线治疗地位已经得到广泛认可，并成为了实体肿瘤分子靶向治疗的经典模型。但同时以上药物的耐药问题一直是临床治疗中的棘手难题和研究热点。许多因素与发生伊马替尼或舒尼替尼耐药有关，其中．KIT／PDGFRA的基因突变是决定耐药与否的主要原因。此外，可能还涉及基因扩增、杂合性丢失和近膜热点区域之外的旁路激活及药物血浆浓度等原因。对于出现肿瘤耐药的患者，应根据不同的耐药原因，采取相应的个体化治疗策略，以期提高治疗效果，改善患者生活质量。

Gastrointestinal stromal tumor（GIST） is the most common mesenchymal neoplasm of the GI tract. Aberrant activation of tyrosine kinase through mutated KIT or plateletderived growth factor receptor（PDGFRA） is the key pathogenic factor in most cases. Tyrosine kinase inhibitors （TKI） such as imatinib and sunitinib can suppress activation of tyrosine kinaase receptor and has gained wide recognition as the firstline adjuvant therapy for advanced or high-risk GIST after surgery. It has become the classic model of treatment for solid tumor with molecular targeted therapy. However, the emergence of drug-resistance limits the long-term benefit of these drugs in most patients and has been a challenging clinical concern.Many faetors are related to the resistance of TKI, of which KIT/PDGFRA mutation is the most important one. Genetic amplification of KIT, loss of heterozygosity, activation of an alternative downstream signaling pathways, and drug concentration are all possible factors. Therefore, reasonable individual treatment strategy and early resistance evaluation for imatiniband sunitinib-resistant GISTs are important to patients with drug resistance in order to improve therapeutic efficacy and quality of life.