The latest research progress of the mechanism of drug resistance to TKIs in clinical treatment of gastrointestinal stromal tumor / 肿瘤

ABSTRACT

Gastrointestinal stromal tumor(GIST)is the most common mesenchymal tumor of the gastrointestinal tract.The pathogenesis of most GIST is driven by the gain-of-function mutations of KIT proto-oncogene receptor tyrosine kinase(c-KIT)or platelet-derived growth factor receptor alpha(PDGFRA)gene.The original clinical treatment for GIST was surgical resection only.With the advent of tyrosine kinase inhibitors(TKIs)represented by imatinib,GIST therapy has entered the era of targeted therapy.TKIs have achieved significant clinical efficacy in GIST treatment.To date,several TKI drugs have been approved for clinical application,which has greatly improved the survival time of GIST patients,but the ensuing drug resistance problem is a difficult problem that requires an urgent solution.Currently,it has been confirmed that the main reason for drug resistance to TKI in GIST is the secondary mutation of different exons of c-KIT or PDGFRA.However,even GIST patients with the same exon mutation still reacts very differently to TKIs,suggesting that there may be other mechanisms acting in parallel with c-KIT and PDGFRA.Thanks to the development and application of molecular biological technologies such as CRISPR gene editing technology,the genetic differences between TKI drug resistant and sensitive GIST are becoming clearer and clearer,and many more new mechanisms have been identified.This paper summarizes the latest research progress of the mechanism of drug resistance to the most commonly used TKIs in the clinical treatment of GIST.