Synthetic Lethal Targeting of CREBBP/EP300 in Head and Neck Squamous Cell Carcinoma

头颈部鳞状细胞癌(HNSCC)是从上到上的一组不同的肿瘤 结果相对较差，靶向治疗选择有限。大多数患者都是 用DNA损伤剂(白金、XRT)的组合治疗。最新的基因组特征 这些肿瘤还没有确定有针对性的致癌驱动因素，因此强调了发展理性的必要性 以基因组为基础的方法，以提高对导致DNA损伤的治疗的敏感性。我们表演了一场 HNSCC细胞株单独或联合应用的活体功能基因组筛选 DNA破坏剂。CREBBP或EP300的敲除被认为是一种潜在的机制 使细胞对DNA损伤反应敏感。CREBBP和EP300是同源的多功能 含有溴域的乙酰转移酶，可以调节许多蛋白质和途径。重要的是 CREBBP和EP300在13%的HNSCC中发生突变，敏感性似乎与这些因素有关 变化，表明这是一种合成细胞毒性关系。此外，这些基因是可用药的，而且很小。 CREBBP的分子抑制增加辐射反应中DNA损伤的诱导和持续时间 治疗和增加细胞凋亡性死亡。我们假设CREBBP/EP300途径既是一种 生物标志物和治疗相关靶点使HNSCC对当前使用的DNA损伤敏感 治疗。我们建议检查这种合成细胞毒性的基因组基础，并了解如何 突变会调节表型。我们还将确定由以下因素引起的组蛋白乙酰化的全球变化 CREBBP或EP300的调节，旨在了解这些变化如何影响对DNA的反应 损坏。此外，调节这些基因的治疗剂将在 临床前模型，目的是产生足够的数据来证明临床试验的合理性。最后，我们将表演 另一种活体筛选，以确定其他靶点，可以敏化抑制CREBBP，降低毒性。 总体而言，该项目将研究一种令人兴奋的新的治疗靶点和肿瘤类型的候选生物标记物。 这是由肿瘤抑制基因的丢失推动的，已被证明很难靶向。

Head and neck squamous cell carcinomas (HNSCC) are a diverse group of tumors from the upper aerodigestive tract with relatively poor outcomes and limited targeted therapeutic options. Most patients are treated with a combination of DNA damaging agents (platinum, XRT). Recent genomic characterization of these tumors has not identified targetable oncogenic drivers, thus emphasizing the need to develop rational genomic-based approaches to increase sensitivity to treatments that induce DNA damage. We performed an in vivo functional genomic screen in genomically characterized HNSCC cell lines alone or in combination with DNA damaging agents. Knock-down of CREBBP or EP300 was identified as a potential mechanism to sensitize cells to the DNA damage response. CREBBP and EP300 are homologous multifunctional bromodomain-containing acetyltransferases that can regulate many proteins and pathways. Importantly, CREBBP and EP300 are mutated in 13% of HNSCC and sensitivity seems to be associated with those alterations, suggesting a synthetic cytotoxicity relationship. Additionally, these genes are druggable and small molecule inhibition of CREBBP increases DNA damage induction and persistence in response to radiation treatment and increased apoptotic cell death. We hypothesize that the CREBBP/EP300 pathway is both a biomarker and a therapeutically relevant target to sensitize HNSCC to currently used DNA damaging treatments. We propose to examine the genomic basis for this synthetic cytotoxicity and understand how mutations modulate the phenotype. We will also identify global changes to histone acetylation caused by modulation of CREBBP or EP300 and aim to understand how those changes impact the response to DNA damage. Additionally, therapeutic agents that modulate these genes will be tested for their efficacy in preclinical models with the goal of generating sufficient data to justify a clinical trial. Finally, we will perform another in vivo screen to identify other targets that can sensitize to inhibition of CREBBP with reduced toxicity. Overall, this project will examine an exciting new therapeutic target and candidate biomarker for a tumor type that is driven by loss of tumor suppressor genes and has proven difficult to target.