Molecular mechanism and therapeutic strategy for resistance to tyrosine kinase inhibitors in targeted treatment of gastrointestinal stromal tumors.
- Author:
Jia XU
1
;
Hui CAO
Author Information
1. Department of General Surgery, Renji Hospital, Jiaotong University, Shanghai 200127, China.
- Publication Type:Journal Article
- MeSH:
Antineoplastic Agents;
therapeutic use;
Benzamides;
therapeutic use;
Drug Resistance, Neoplasm;
genetics;
Gastrointestinal Neoplasms;
drug therapy;
genetics;
Gastrointestinal Stromal Tumors;
drug therapy;
genetics;
Humans;
Imatinib Mesylate;
Indoles;
therapeutic use;
Mutation;
Piperazines;
therapeutic use;
Protein Kinase Inhibitors;
therapeutic use;
Proto-Oncogene Proteins c-kit;
genetics;
Pyrimidines;
therapeutic use;
Pyrroles;
therapeutic use;
Receptor, Platelet-Derived Growth Factor alpha;
genetics
- From:
Chinese Journal of Gastrointestinal Surgery
2013;16(3):288-291
- CountryChina
- Language:Chinese
-
Abstract:
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the GI tract. Aberrant activation of tyrosine kinase through mutated KIT or platelet-derived 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 kinase receptor and has gained wide recognition as the first-line 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 factors 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 imatinib- and sunitinib-resistant GISTs are important to patients with drug resistance in order to improve therapeutic efficacy and quality of life.
