Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic KIT mutations that are effectively targeted by imatinib (IM), a tyrosine kinase inhibitor (TKI). However, IM does not cure GIST, and adjuvant therapy only delays recurrence in high-risk tumors. We hypothesized that GIST contains cells with primary IM resistance that may represent a reservoir for disease persistence. Here, we report a subpopulation of CD34+KITlow human GIST cells that have intrinsic IM resistance. These cells possess cancer stem cell-like expression profiles and behavior, including self-renewal and differentiation into CD34+KIThigh progeny that are sensitive to IM treatment. We also found that TKI treatment of GIST cell lines led to induction of stem cell–associated transcription factors ( OCT4 and NANOG ) and concomitant enrichment of the CD34+KITlow cell population. Using a data-driven approach, we constructed a transcriptomic-oncogenic map (Onco-GPS) based on the gene expression of 134 GIST samples to define pathway activation during GIST tumorigenesis. Tumors with low KIT expression had overexpression of cancer stem cell gene signatures consistent with our in vitro findings. Additionally, these tumors had activation of the Gas6/AXL pathway and NF-κB signaling gene signatures. We evaluated these targets in vitro and found that primary IM-resistant GIST cells were effectively targeted with either single-agent bemcentinib (AXL inhibitor) or bardoxolone (NF-κB inhibitor), as well as with either agent in combination with IM. Collectively, these findings suggest that CD34+KITlow cells represent a distinct, but targetable, subpopulation in human GIST that may represent a novel mechanism of primary TKI resistance, as well as a target for overcoming disease persistence following TKI therapy. This article is featured in Highlights of This Issue, [p. 1755][1] [1]: /lookup/volpage/20/1755?iss=10

中文翻译：

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KITlow 细胞介导胃肠道间质瘤的伊马替尼耐药性


胃肠道间质瘤 (GIST) 通常由致癌 KIT 突变驱动，而伊马替尼 (IM)（一种酪氨酸激酶抑制剂 (TKI)）可有效靶向该突变。然而，IM 并不能治愈 GIST，辅助治疗只能延缓高危肿瘤的复发。我们假设 GIST 含有具有原发性 IM 耐药性的细胞，这些细胞可能是疾病持续存在的储存库。在这里，我们报告了具有内在 IM 抵抗性的 CD34+KITlow 人类 GIST 细胞亚群。这些细胞具有癌症干细胞样的表达谱和行为，包括自我更新和分化为对 IM 治疗敏感的 CD34+KIThigh 后代。我们还发现，TKI 治疗 GIST 细胞系可诱导干细胞相关转录因子（OCT4 和 NANOG）的诱导，并伴随 CD34+KITlow 细胞群的富集。使用数据驱动的方法，我们基于 134 个 GIST 样本的基因表达构建了转录组致癌图谱 (Onco-GPS)，以定义 GIST 肿瘤发生过程中的通路激活。 KIT 表达低的肿瘤具有癌症干细胞基因特征的过度表达，这与我们的体外研究结果一致。此外，这些肿瘤还激活了 Gas6/AXL 通路和 NF-κB 信号基因特征。我们在体外评估了这些靶标，发现单药 bemcentinib（AXL 抑制剂）或 bardoxolone（NF-κB 抑制剂）以及任一药物与 IM 联合使用均可有效靶向原代 IM 耐药性 GIST 细胞。总的来说，这些发现表明 CD34+KITlow 细胞代表了人类 GIST 中独特但可靶向的亚群，可能代表了原发性 TKI 耐药的新机制，以及克服 TKI 治疗后疾病持续存在的目标。 本文收录于本期亮点，[p. 11]。 1755][1][1]：/lookup/volpage/20/1755？国际空间站=10