伊马替尼甲磺酸盐（IM）在胃肠道间质瘤（GIST）的治疗中引起了革命。然而，多数患者最终都会产生IM耐药性。第二线和第三线治疗在临床上仅表现出温和的疗效，疾病进展的中位数时间为4-6个月，这突显了对新型治疗方法的紧迫性。在这里，我们报告了在IM治疗后GIST细胞中已知的致癌驱动基因和转录抑制剂BCL6的表达显著增加。升高的BCL6水平抑制了细胞凋亡，并促进了对IM的耐药性。从机制上讲，BCL6将SIRT1招募到TP53启动子上，调节了组蛋白乙酰化和转录抑制TP53的表达。p53的减少进一步减弱了细胞凋亡并促进了GIST细胞对IM的耐受性。符合一致的是，对于BCL6表达水平较高的GIST细胞，使用BCL6抑制剂BI-3802使其对IM具有敏感性。此外，BI-3802在体外和体内显示出与IM在对IM敏感和IM耐药的GIST细胞中的显著协同作用。因此，这些发现揭示了BCL6在IM耐药性中的作用，并提示BCL6抑制剂与IM的联合可能是GIST的一种潜在有效治疗方法。

Imatinib mesylate (IM) has revolutionized the treatment of gastrointestinal stromal tumor (GIST). However, most patients inevitably acquire IM resistance. Second- and third-line treatments exhibit modest clinical benefits with a median time to disease progression of 4-6 months, highlighting the urgency for novel therapeutic approaches. Here, we report that the expression of BCL6, a known oncogenic driver and transcriptional repressor, was significantly induced in GIST cells following IM treatment. Elevated BCL6 levels suppressed apoptosis and contributed to IM resistance. Mechanistically, BCL6 recruited SIRT1 to the TP53 promoter to modulate histone acetylation and transcriptionally repress TP53 expression. The reduction in p53 subsequently attenuated cell apoptosis and promoted tolerance of GIST cells to IM. Concordantly, treatment of GIST cells showing high BCL6 expression with a BCL6 inhibitor, BI-3802, conferred IM sensitivity. Furthermore, BI-3802 showed striking synergy with IM in IM-responsive and IM-resistant GIST cells in vitro and in vivo. Thus, these findings reveal a role for BCL6 in IM resistance and suggest that a combination of BCL6 inhibitors and IM could be a potentially effective treatment for GIST.