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Cyclin D1 is a mediator of gastrointestinal stromal tumor KIT-independence.
Oncogene ( IF 6.9 ) Pub Date : 2019-08-01 , DOI: 10.1038/s41388-019-0894-3 Wen-Bin Ou 1, 2 , Nan Ni 1 , Rui Zuo 1 , Weihao Zhuang 1 , Meijun Zhu 2 , Anastasios Kyriazoglou 2 , Duolin Wu 1 , Grant Eilers 2 , George D Demetri 3 , Haibo Qiu 2, 4 , Bin Li 2, 5 , Adrian Marino-Enriquez 2 , Jonathan A Fletcher 2
Oncogene ( IF 6.9 ) Pub Date : 2019-08-01 , DOI: 10.1038/s41388-019-0894-3 Wen-Bin Ou 1, 2 , Nan Ni 1 , Rui Zuo 1 , Weihao Zhuang 1 , Meijun Zhu 2 , Anastasios Kyriazoglou 2 , Duolin Wu 1 , Grant Eilers 2 , George D Demetri 3 , Haibo Qiu 2, 4 , Bin Li 2, 5 , Adrian Marino-Enriquez 2 , Jonathan A Fletcher 2
Affiliation
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Oncogenic KIT or PDGFRA tyrosine kinase mutations are compelling therapeutic targets in most gastrointestinal stromal tumors (GISTs), and the KIT inhibitor, imatinib, is therefore standard of care for patients with metastatic GIST. However, some GISTs lose expression of KIT oncoproteins, and therefore become KIT-independent and are consequently resistant to KIT-inhibitor drugs. We identified distinctive biologic features in KIT-independent, imatinib-resistant GISTs as a step towards identifying drug targets in these poorly understood tumors. We developed isogenic GIST lines in which the parental forms were KIT oncoprotein-dependent, whereas sublines had loss of KIT oncoprotein expression, accompanied by markedly downregulated expression of the GIST biomarker, protein kinase C-theta (PRKCQ). Biologic mechanisms unique to KIT-independent GISTs were identified by transcriptome sequencing, qRT-PCR, immunoblotting, protein interaction studies, knockdown and expression assays, and dual-luciferase assays. Transcriptome sequencing showed that cyclin D1 expression was extremely low in two of three parental KIT-dependent GIST lines, whereas cyclin D1 expression was high in each of the KIT-independent GIST sublines. Cyclin D1 inhibition in KIT-independent GISTs had anti-proliferative and pro-apoptotic effects, associated with Rb activation and p27 upregulation. PRKCQ, but not KIT, was a negative regulator of cyclin D1 expression, whereas JUN and Hippo pathway effectors YAP and TAZ were positive regulators of cyclin D1 expression. PRKCQ, JUN, and the Hippo pathway coordinately regulate GIST cyclin D1 expression. These findings highlight the roles of PRKCQ, JUN, Hippo, and cyclin D1 as oncogenic mediators in GISTs that have converted, during TKI-therapy, to a KIT-independent state. Inhibitors of these pathways could be effective therapeutically for these now untreatable tumors.
中文翻译：
细胞周期蛋白D1是胃肠道间质瘤KIT独立的介质。
致癌性KIT或PDGFRA酪氨酸激酶突变是大多数胃肠道间质瘤（GIST）的引人注目的治疗靶标，因此KIT抑制剂伊马替尼是转移性GIST患者的标准治疗方法。但是，某些GIST会失去KIT癌蛋白的表达，因此变得不依赖KIT，因此对KIT抑制剂药物具有抗性。我们在不依赖KIT的伊马替尼耐药GIST中鉴定出独特的生物学特征，以此作为在这些鲜为人知的肿瘤中鉴定药物靶标的步骤。我们开发了同基因的GIST品系，其亲本形式是KIT癌蛋白依赖性的，而子系具有KIT癌蛋白表达的损失，并伴随着GIST生物标志物蛋白激酶C-theta（PRKCQ）的表达明显下调。通过转录组测序，qRT-PCR，免疫印迹，蛋白质相互作用研究，敲除和表达测定以及双萤光素酶测定确定了不依赖于KIT的GIST的独特生物学机制。转录组测序显示，在三个亲本KIT依赖的GIST系中的两个中，细胞周期蛋白D1的表达极低，而在每个不依赖KIT的GIST子系中，细胞周期蛋白D1的表达都很高。在不依赖KIT的GIST中抑制细胞周期蛋白D1具有抗增殖和促凋亡作用，与Rb激活和p27上调相关。PRKCQ，而不是KIT，是细胞周期蛋白D1表达的负调节剂，而JUN和Hippo通路效应子YAP和TAZ是细胞周期蛋白D1表达的正调节剂。PRKCQ，JUN和Hippo通路协调调节GIST cyclin D1的表达。这些发现凸显了PRKCQ，JUN，河马和细胞周期蛋白D1在GIST中的致癌介质中的作用，这些TIST在TKI治疗期间已转变为不依赖KIT的状态。这些途径的抑制剂对于这些现在无法治疗的肿瘤可能在治疗上是有效的。
更新日期：2019-08-01
中文翻译：
细胞周期蛋白D1是胃肠道间质瘤KIT独立的介质。
致癌性KIT或PDGFRA酪氨酸激酶突变是大多数胃肠道间质瘤（GIST）的引人注目的治疗靶标，因此KIT抑制剂伊马替尼是转移性GIST患者的标准治疗方法。但是，某些GIST会失去KIT癌蛋白的表达，因此变得不依赖KIT，因此对KIT抑制剂药物具有抗性。我们在不依赖KIT的伊马替尼耐药GIST中鉴定出独特的生物学特征，以此作为在这些鲜为人知的肿瘤中鉴定药物靶标的步骤。我们开发了同基因的GIST品系，其亲本形式是KIT癌蛋白依赖性的，而子系具有KIT癌蛋白表达的损失，并伴随着GIST生物标志物蛋白激酶C-theta（PRKCQ）的表达明显下调。通过转录组测序，qRT-PCR，免疫印迹，蛋白质相互作用研究，敲除和表达测定以及双萤光素酶测定确定了不依赖于KIT的GIST的独特生物学机制。转录组测序显示，在三个亲本KIT依赖的GIST系中的两个中，细胞周期蛋白D1的表达极低，而在每个不依赖KIT的GIST子系中，细胞周期蛋白D1的表达都很高。在不依赖KIT的GIST中抑制细胞周期蛋白D1具有抗增殖和促凋亡作用，与Rb激活和p27上调相关。PRKCQ，而不是KIT，是细胞周期蛋白D1表达的负调节剂，而JUN和Hippo通路效应子YAP和TAZ是细胞周期蛋白D1表达的正调节剂。PRKCQ，JUN和Hippo通路协调调节GIST cyclin D1的表达。这些发现凸显了PRKCQ，JUN，河马和细胞周期蛋白D1在GIST中的致癌介质中的作用，这些TIST在TKI治疗期间已转变为不依赖KIT的状态。这些途径的抑制剂对于这些现在无法治疗的肿瘤可能在治疗上是有效的。
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