Lessons from Structural Biology for Understanding Drug Resistance in Gastrointestinal Stromal Tumors (GIST)

Gastrointestinal stromal tumors (GISTs) are primarily driven by activating mutations in the receptor tyrosine kinases KIT or PDGFRA. Targeted therapies have significantly improved patient outcomes; however, acquired drug resistance continues to limit long-term efficacy. Secondary and tertiary mutations across distinct regions of the kinase domain affect the conformational equilibrium or directly disrupt drug binding by alteration of critical residues. This perspective highlights key structural insights that elucidate the molecular basis of resistance and its interplay with kinase activation and TKI binding. A comprehensive understanding of these molecular alterations is crucial for guiding future therapeutic strategies to overcome resistance.