INTRODUCTION: 90% of gastrointestinal stromal tumors (GISTs) harbor an 
activating mutation in the KIT or PDGFRα oncogene, and these are known to confer 
imatinib sensitivity.
AREAS COVERED: The author reviews the data regarding the current management of 
GIST, mechanisms of resistance to imatinib, and new drugs currently in clinical 
development and provides his unique perspectives on the subject matter.
EXPERT OPINION: Several studies have shown that the response to imatinib in GIST 
patients mainly depends on the mutational status of KIT or PDGFRα. Moreover, 
most, if not all, patients treated with imatinib for advanced GIST will develop 
a secondary progressive disease under the treatment. In most cases, such 
progressions are the result of acquired resistance due to the occurrence of 
secondary c-KIT mutations, especially in GISTs with primary exon 11 mutations. 
Sunitinib and regorafenib are inhibitors of multiple tyrosine kinases, including 
KIT, PDGFRα, PDGFRβ, and VEGFRs, and are approved for the management of 
imatinib- and imatinib/sunitinib-refractory GIST patients, respectively. 
Clearly, better knowledge of the molecular mechanisms underlying the resistance 
to imatinib as well as the development of a new class of broad-spectrum tyrosine 
kinase inhibitors such as avapritinib and ripretinib will provide new 
individualized therapeutic strategies for GIST patients.