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

SMARCA 4/BRG 1的功能缺失突变，SMARCA 4/BRG 1是一种肿瘤抑制因子和核心成分， SWI/SNF染色质重塑复合物，经常发生在肺腺癌（LAD）和 预后很差作为一种肿瘤抑制因子，BRG 1的畸变没有有效的治疗方法。 Hedgehog（Hh）信号转导的转录因子和靶基因GLI 1的调节 已经报道了通过替代途径的GLI 1的高表达与 非小细胞肺癌患者的生存率明显较差。BRG 1-已显示损失 在小鼠胚胎成纤维细胞中独立于Hh通路上调GLI 1。然而，在这方面， 在肺癌中还没有这类研究的报道。我们发现GLI 1的高表达在 LAD细胞系依赖于BRG 1的缺失。GLI 1表达的遗传和药理学抑制 抑制BRG 1缺陷型肺癌细胞系的生长并诱导细胞死亡。所以我们 假设BRG 1的缺失上调GLI 1表达以驱动LAD生长， GLI 1是BRG 1缺陷型LAD的候选治疗靶点。建议的理由 研究是阐明BRG 1缺失上调GLI 1的机制 表达将鉴定新的治疗候选物，其调节将抑制 BRG 1缺陷型肺癌中的GLI 1转录因子--一种不容易 可操作的治疗目标。我们建议通过以下方法来确定GLI 1抑制的机制： BRG 1和GLI 1表达上调与BRG 1损失。我们还将测试三种治疗方法 用FDA批准的或在临床上有效的药物抑制GLI 1表达的方案 试验.我们利用一种新的自体小鼠模型和患者来源的BRG 1- 左前降支缺陷来测试治疗方案我们还将识别错义和无义突变， 上调GLI 1表达，因此可作为治疗的预测性生物标志物 在这里测试。如果成功，我们的结果将为靶向BRG 1建立坚实的科学依据。 具有抑制GLI 1表达的化合物的缺陷型肺癌 用于临床试验。

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.