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

点击翻译按钮获取中文摘要

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.