Aptamer-based drug delivery for targeted therapy of imatinib-resistant gastrointestinal stromal tumor

<b>Rationale:</b> Gastrointestinal stromal tumors (GIST), the most common mesenchymal tumors of the gastrointestinal tract, are primarily driven by activating mutations in the KIT intracellular segment. The standard treatment with imatinib frequently results in acquired resistance due to secondary mutations. Besides mutations, KIT is also overexpressed in GIST. An aptamer that specifically binds to the extracellular segment of KIT (unaffected by these mutations) was promising in drug delivery and may overcome imatinib resistance. <b>Methods:</b> The microtubule inhibitor VcMMAE (mc-vc-PAB-MMAE) was conjugated with an optimized KIT-targeting aptamer (KIT-d) to generate an aptamer-drug conjugate (ApDC) named KIT-d-MMAE. This ApDC was then evaluated for its binding specificity, internalization via endocytosis, and cytotoxicity towards KIT-positive GIST cells. The therapeutic efficacy of KIT-d-MMAE was evaluated through both <i>in vitro</i> and <i>in vivo</i> experiments. <b>Results:</b> KIT-d-MMAE exhibited specific binding and efficient internalization into KIT-positive GIST cells, including imatinib-resistant lines, inducing targeted cytotoxic effects. In animal studies, KIT-d-MMAE significantly suppressed tumor growth in GIST-T1 subcutaneous and liver metastasis models. Notably, in imatinib-resistant GIST-430/654 and multi-TKI-resistant patient-derived xenograft (PDX) models, KIT-d-MMAE demonstrated superior antitumor efficacy compared to imatinib. Additionally, therapeutic effects were also observed in genetically engineered mouse models, indicating effective inhibition of spontaneous tumor formation and progression. <b>Conclusion:</b> The aptamer-based drug delivery not only provides an innovative approach to overcome drug resistance but also simplifies treatment regimens, offering new therapeutic hope and marking a significant advancement in targeted therapy for GIST patients.