Therapeutic Strategies after Imatinib Resistance in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumor (GIST) is a mesenchymal tumor commonly found in the gastrointestinal tract and its pathogenesis is mainly associated with c-KIT and PDGFRA gene mutations. Surgery is the standard treatment for limited GIST, while imatinib (IM) is the first-line treatment for patients with advanced or unresectable GIST. However, imatinib resistance (both primary and secondary resistance) remains a major challenge in the treatment of GIST. To address this challenge, the second-line drug sunitinib, the third-line drug regorafenib, and the fourth-line drug Ripretinib, as well as avapritinib targeting the PDGFRA D842V mutation, have been introduced into the clinic. In addition, therapeutic agents for wild-type GIST, such as SDH-deficient, NTRK-fusion and BRAF V600E mutant, have shown initial efficacy. Next-generation TKIs and other therapeutic strategies (e.g., heat shock protein inhibitors, mTOR inhibitors, immunotherapy) are still being explored, bringing new hope to patients with advanced drug-resistant GIST. In the future, the in-depth study of drug resistance mechanisms, the development of personalized treatment regimens, and the exploration of combination therapies will hopefully further improve the survival and quality of life of GIST patients.