The canonical mutations in gastrointestinal stromal tumors (GISTs) are typically activating mutations in KIT and platelet-derived growth factor receptor alpha (PDGFRA). GISTs with non-canonical mutations are a heterogeneous group. Here, we examined tropomyosin-related kinase (TRK) fusion in GIST cases without KIT/PDGFRA mutations (KIT/PDGFRA wild-type (WT) GISTs). We retrospectively analyzed patients who were diagnosed with GISTs at the Yonsei Cancer Center, Severance Hospital, between January 1998 and December 2016. Thirty-one patients with KIT/PDGFRA WT GISTs were included in the analysis. TRK expression in tumor samples was assessed by pan-TRK immunohistochemistry (IHC), and the neurotrophic tyrosine receptor kinase (NTRK: the gene encoding TRK) rearrangement was analyzed by fluorescence in situ hybridization (FISH). IHC analyses revealed that five cases in this cohort exhibited a weak to moderate TRK expression. NTRK1 fusions were detected in three tumor samples, and two samples harbored NTRK3 fusions. The remaining 26 samples did not harbor NTRK fusions. Two types of NTRK fusions were detected, and the overall NTRK fusion frequency in KIT/PDGFRA WT GIST cases was 16% (5/31). Our data provide insights into the molecular alterations underpinning KIT/PDGFRA WT GISTs. More effort should be devoted to improve methods to identify this distinct disease subtype within the KIT/PDGFRA WT GIST group.

Background/Objectives: Irinotecan, a camptothecin (CPT) derivative, is commonly used as a first-line therapy for colorectal cancer (CRC), but resistance remains a significant challenge. This study aims to explore the therapeutic potential of FL118, another CPT derivative, with a focus on overcoming resistance to irinotecan. Methods: The effects of FL118 on CRC cells were evaluated, and bioinformatics analysis was performed on RNA-seq data. Transfection was conducted to observe the knockdown effect of survivin, and the in vivo efficacy of FL118 was assessed using a xenograft model. Results: FL118 induces apoptosis, G2/M arrest, and DNA damage. A notable mechanism of action of FL118 is a reduction in survivin levels, which downregulates the expression of RAD51, a key marker of homologous recombination, and attenuates DNA repair processes. Given that SN38 is the active metabolite of irinotecan, FL118 reduces cell viability and RAD51 in SN38-resistant LOVO cells. Conclusions: Our findings provide effective insights into the antitumor activity of FL118 and its potential as a therapeutic agent for overcoming irinotecan resistance in CRC.