GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE240nnn/GSE240411/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE240411GEOGSEfalseIdentification of potential targets of FTO in GIST via transcriptome-wide RNA-seqTyrosine kinase inhibitor (TKIs) resistance remains the leading obstacle for treating gastrointestinal stromal tumor (GIST), in which the secondary mutations within KIT causes escape of TKI inhibition and KIT reactivation. Here we found FTO was highly expressed in GIST and positively correlated with the high-grade and recurrence liability. m6A-seq and RNA-seq analyses of GIST cells treated with FTO inhibitor CS1 demonstrated that FTO demethylated the m6A modification in the 3’UTR of KIT mRNA, which in turn partially blocked recognition by m6A reader YTHDF2, thus enhanced KIT mRNA stability. Pharmacological inhibition or genetic knockdown of FTO led to decreased KIT expression, mitigated malignant phenotypes and increased imatinib sensitivity in vitro, while genetic knockout of FTO or entacapone treatment combined with imatinib evoked regression of tumor in KIT-Asp818Tyr/+ heterozygote GIST mouse model. Phase I trial in five TKIs-refractory GIST patients with a combination of entacapone and imatinib (NCT 04006769) demonstrated that two of three assessable participants (66.7%) achieved partial remission. Our results suggest that targeting FTO is a feasible therapeutic strategy for clinical management of TKI resistance and recurrence of GIST.2026/06/10GSE240411GSM7697660GSM7697671GSM7697661GSM7697672GSM7697670GSM7697664GSM7697653GSM7697675GSM7697665GSM7697676GSM7697654GSM7697662GSM7697673GSM7697674GSM7697663GSM7697657GSM7697668GSM7697658GSM7697669GSM7697655GSM7697666GSM7697667GSM7697656GSM769765924676240411Homo sapiens