Decreased M6A Modification Promotes Progression of Gastrointestinal Stromal Tumor and KIT‐Derived Imatinib Resistance Through FTO‐Regulated Axis

ABSTRACT Imatinib (IM) is the first‐line therapy for high‐risk gastrointestinal stromal tumor (GIST) patients; however, over 50% of those with advanced stage or metastasis develop IM resistance within 2 years, and effective strategies to overcome this resistance remain elusive. In this study, we identified that decreased N 6‐methyladenosine (m6A) modification by the demethylase FTO regulated GIST progression and IM resistance. Long noncoding RNA XIST (XIST) was identified as the main demethylated RNA by FTO in GIST. FTO leaded to a decrease in m6A modification at the 10517‐10633 site of XIST, thereby protecting it from degradation mediated by YTHDF2's recognition and binding. Stabilized XIST enhanced IM resistance by acting as a posttranscriptional regulator of KIT, the primary oncogenic driver in GIST. In vitro and in vivo functional assays confirmed the roles of both FTO and XIST in promoting GIST progression and IM resistance. Importantly, pharmacological inhibition of FTO using FB23‐2 effectively restored IM sensitivity in murine xenograft models of GIST. Together, our findings establish a mechanistic link among FTO‐mediated m6A demethylation, XIST stabilization, and posttranscriptional regulation of KIT in GIST. These insights highlight the therapeutic potential of targeting m6A‐FTO axis to overcome IM resistance in GIST treatment.