KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem

Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations.