胃肠道间质瘤伊马替尼继发耐药治疗的研究进展

Advances in Management of Gastrointestinal Stromal Tumors with Secondary Resistance to Imatinib

酪氨酸激酶抑制剂伊马替尼在胃肠道间质瘤(GISTs)的治疗中已取得令人瞩目的疗效,然而伊马替尼继发耐药的出现成为亟待解决的临床难题。GISTs对伊马替尼继发耐药的可能机制包括KIT/PDGFRA基因二次突变、PTEN基因丢失、触发GIST细胞进入静止期等。针对上述耐药机制,目前已提出新型酪氨酸激酶抑制剂、联合应用下游通路靶向抑制剂、较少依赖KIT/PDGFRA途径的靶向抑制剂(KIT分子伴侣抑制剂、极光激酶抑制剂等)、诱导静止期GIST细胞凋亡等解决伊马替尼继发耐药的策略,本文就相关研究进展作一综述。

The use of tyrosine kinase inhibitor imatinib in treatment of gastrointestinal stromal tumors（GISTs）has achieved a dramatic therapeutic efficacy. However,secondary imatinib resistance emerged as a clinical problem needs to be solved urgently. The underlying mechanisms of GISTs secondary resistance to imatinib may be related with secondary mutations of KIT/ PDGFRA genes,loss of PTEN gene and induction of cellular quiescence. This resulted in the adoption of new therapeutic strategies such as novel tyrosine kinase inhibitors,combined use of imatinib with downstream signaling inhibitors,KIT/ PDGFRA independent targeted inhibitors such as KIT chaperone inhibitors and aurora kinase inhibitors,as well as inducing apoptosis in quiescent GIST cells. In this article,the above-mentioned issues were summarized.