Regulation of GLI1, a synthetic lethal target of SMARCA4-deficiency, in lung adenocarcinoma

肿瘤抑制基因SMARCA4/BRG1功能突变缺失 SWI/SNF染色质重塑复合体在肺腺癌(LAD)和 港湾预后不佳。作为一种肿瘤抑制基因，BRG1基因的异常没有可操作的治疗方法。 Hedgehog(HH)信号转导的转录因子和靶基因GLI1的调控 GLI1高表达与GLI1的高表达相关 具有明显低生存率的非小细胞肺癌患者。BRG1-已显示亏损 上调小鼠胚胎成纤维细胞中不依赖于HH途径的GLI1。然而， 目前还没有关于肺癌的此类研究的报道。我们发现GLI1在细胞中的高表达。 LAD细胞系依赖BRG1-Lost。GLI1表达的遗传和药物抑制 抑制BRG1基因缺陷肺癌细胞株的生长和诱导细胞死亡。因此，我们 假设BRG1的缺失上调GLI1的表达以驱动LAD的生长，并且 Gli1是BRG1缺陷LAD的候选治疗靶点。建议的理由是 研究是阐明BRG1缺失上调GLI1的机制 表达将识别其调节将抑制其表达的新的候选治疗 BRG1缺陷型肺癌中GLI1转录因子的表达 可操作的治疗目标。我们建议通过以下方式确定抑制GLI1的机制 BRG1及BRG1缺失时GLI1表达上调。我们还将测试三种治疗方法 用FDA批准的或正在进行临床试验的药物抑制GLI1表达的方案 测试。我们利用一种新的自体小鼠模型和患者来源的BRG1异种移植- 没有足够的小伙子来测试这些养生法。我们还将识别错义和无义突变 上调GLI1的表达，因此可以作为治疗的预测生物标志物 在这里测试过。如果成功，我们的结果将为靶向BRG1- 具有抑制GLI1表达的化合物且易于获得的缺陷性肺癌 用于临床测试。

Loss of function mutations in SMARCA4/BRG1, a tumor suppressor and core component of SWI/SNF chromatin remodeling complexes, occur frequently in lung adenocarcinoma (LAD) and harbor a poor prognosis. As a tumor suppressor, aberrations of BRG1 have no actionable therapy. Modulation of GLI1, a transcription factor and target gene of the Hedgehog (Hh) signaling pathway, by alternative pathways has been reported and high expression of GLI1 is correlated with significantly poor survival of non-small cell lung cancer patients. BRG1-loss has been shown to up-regulate GLI1 independently of the Hh pathway in mouse embryonic fibroblasts. However, no such studies have been reported in lung cancers. We show that high expression of GLI1 in LAD cell lines depend upon BRG1-loss. Genetic and pharmacologic inhibition of GLI1 expression inhibit the growth and induce cell death in BRG1-deficient lung cancer cell lines. Therefore, we HYPOTHESIZE that loss of BRG1 upregulates GLI1 expression to drive LAD growth and that GLI1 is a candidate therapeutic target for BRG1-deficient LAD. The rationale for the proposed research is that elucidation of the mechanisms by which loss of BRG1 upregulates GLI1 expression will identify novel therapeutic candidates whose modulation will inhibit expression of the GLI1 transcription factor in BRG1-deficient lung cancers – a cancer type that has no readily actionable target for treatment. We propose to identify mechanisms for GLI1 suppression by BRG1 and for upregulation of GLI1 expression with BRG1 loss. We will also test three therapeutic regimens that inhibit GLI1 expression with drugs that are FDA-approved or in active clinical testing. We utilize a novel autochthonous mouse model and patient derived xenografts of BRG1- deficient LAD to test the regimens. We will also identify missense and nonsense mutations that upregulates GLI1 expression and thus, may serve as predictive biomarkers for the therapies tested here. If successful, our results will establish a firm scientific rationale for targeting BRG1- deficient lung cancers with compounds that inhibit GLI1 expression and that are readily available for clinical testing.