胃肠间质瘤（GIST）常常表现出KIT基因的突变，伴随突变形式的KIT（MT-KIT）的过表达和异常定位。正如我们之前的多项研究所确定的那样，我们证实MT-KIT在高尔基体中启动下游信号传导。基础亮氨酸拉链核转录因子1（BLZF1）被确定为一种新的与MT-KIT结合的伴侣蛋白，它将MT-KIT系留在高尔基体中。持续激活已激活转录因子6（ATF6），后者属于未折叠蛋白反应（UPR）家族，通过上调伴侣蛋白表达，包括热休克蛋白90（HSP90）来减轻内质网（ER）应激，帮助MT-KIT正确折叠。BLZF1沉默和ATF6抑制剂能够在体外抑制耐伊马替尼和敏感的GIST。ATF6抑制剂在GIST移植瘤中也显示出有效的抗肿瘤效果，并且与引起ER应激的药物共同使用时效果更好。在67％的GIST患者（n = 42）中，频繁观察到ATF6激活，并且与较差的无复发生存率显著相关（P = 0.033）。总体而言，GIST通过UPR激活绕过ER质量控制（QC）和ER应激介导的细胞死亡，并利用不受QC限制的高尔基体启动信号转导。© 2023. 作者。

Gastrointestinal stromal tumors (GISTs) frequently show KIT mutations, accompanied by overexpression and aberrant localization of mutant KIT (MT-KIT). As previously established by multiple studies, including ours, we confirmed that MT-KIT initiates downstream signaling in the Golgi complex. Basic leucine zipper nuclear factor 1 (BLZF1) was identified as a novel MT-KIT-binding partner that tethers MT-KIT to the Golgi complex. Sustained activation of activated transcription factor 6 (ATF6), which belongs to the unfolded protein response (UPR) family, alleviates endoplasmic reticulum (ER) stress by upregulating chaperone expression, including heat shock protein 90 (HSP90), which assists in MT-KIT folding. BLZF1 knockdown and ATF6 inhibition suppressed both imatinib-sensitive and -resistant GIST in vitro. ATF6 inhibitors further showed potent antitumor effects in GIST xenografts, and the effect was enhanced with ER stress-inducing drugs. ATF6 activation was frequently observed in 67% of patients with GIST (n = 42), and was significantly associated with poorer relapse-free survival (P = 0.033). Overall, GIST bypasses ER quality control (QC) and ER stress-mediated cell death via UPR activation and uses the QC-free Golgi to initiate signaling.© 2023. The Author(s).