New Vulnerabilities in MYC-Driven Breast Cancer

MYC 驱动的乳腺癌中的新漏洞

• 批准号: 10333228
• 负责人: Thomas Westbrook
• 金额: $ 53.8万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-05 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333228
• 关键词: Animal Model; Animals; Antiviral Response; Apoptosis; Apoptotic; Biological; Breast Cancer Cell; Breast Cancer Patient; Cancer Patient; Cell Death; Cellular Stress; Clinic; Clinical Trials; DNA Damage; Data; Defect; Diagnosis; Double-Stranded RNA; Evaluation; Gene Expression; Genes; Genetic; Genetic Engineering; Genetic Screening; Genetic Transcription; Genome; Genomics; Human; Immune signaling; Impairment; Innate Immune System; Introns; Link; MYC gene; Malignant Neoplasms; Messenger RNA; Methods; Microscopy; Molecular; Nature; Oncogenes; Oncogenic; Pathway interactions; Patient Care; Patient-derived xenograft models of breast cancer; Pharmacology; Pre-Clinical Model; Process; Prognosis; Proteins; Proteome; Proteomics; Proto-Oncogene Proteins c-myc; RNA; RNA Folding; RNA Interference; RNA Splicing; RNA interference screen; RNA metabolism; Research; Role; Science; Shapes; Signal Pathway; Signal Transduction; Source; Spliceosomes; Stress; Structure; Therapeutic; Work; biological adaptation to stress; breast cancer survival; cancer cell; cancer type; cell behavior; cohort; combat; forward genetics; gene discovery; gene network; genetic inhibitor; in vivo; inhibitor; innate immune pathways; insight; mRNA Precursor; malignant breast neoplasm; neoplastic cell; next generation sequencing; novel; novel therapeutics; pathogenic virus; patient derived xenograft model; refractory cancer; response; sensor; single molecule; small molecule; targeted treatment; transcription factor; transcriptome; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor progression; tumorigenesis; whole genome

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with more than 200,000 new diagnoses each year. The oncogene Myc is a common driver of TNBC. However, despite important research into the biologic and molecular functions of Myc, no tractable therapies have emerged to inhibit this oncogenic transcription factor. TNBC and other Myc-driven cancers remain recalcitrant to current targeted therapies, underlining the urgent need to identify new vulnerabilities in these malignancies. In addition to promoting tumorigenesis, oncogenes such as Myc also produce unique stresses in cancer cells, collectively termed oncogenic stress. Using parallel whole-genome RNAi screens, we discovered that Myc imposes a new type of oncogenic stress on TNBCs that we term RNA splicing stress, or RSS (Kessler, Science 2012; Hsu, Nature 2015). In many cancer types, Myc (or other oncogenic insults) globally amplifies transcription leading to increased pre-mRNA burden on the spliceosome. Consequently, Myc-driven TNBCs are exquisitely sensitive to modest perturbations in the spliceosome (by enhancing RSS). Importantly, pharmacologic or genetic inhibitors of the spliceosome impair primary and metastatic progression of TNBC and are well tolerated in animal pre-clinical models. While spliceosome inhibitors have entered clinical trials, the mechanisms by which RSS and spliceosome inhibitors selectively kill cancer cells are unknown. Herein, we propose to discover the pathway(s) sensing and responding to RNA splicing stress and to delineate the mechanisms by which RSS triggers cancer cell death. Aim 1: Delineate the dsRNA-sensing pathways (DSP’s) stimulated by RSS in Myc+ TNBCs in vivo. Our preliminary data suggest that RSS induces TNBC apoptosis by triggering innate immune pathways that detect and respond to dsRNAs. By leveraging a TNBC PDX cohort with new genetic and proteomic platforms, we will determine how DSP’s and other stress response pathways are activated in response to spliceosome inhibition. Aim 2: Discover how RSS triggers dsRNA-sensing pathways in TNBCs. Many viral pathogens encode dsRNA genomes that are detected by dsRNA-sensors of the innate immune system. Our studies indicate RSS leads to cytoplasmic accumulation of intron-retained mRNAs, a potential source of dsRNAs. Using new sequencing and single-molecule microscopy methods, we will study the mechanisms by which RSS shapes the secondary structure and subcellular localization of TNBC transcriptomes and stimulates dsRNA-sensors. Aim 3: Delineate how DSPs and other stress response pathways govern TNBC response to spliceosome inhibitors. We hypothesize that there is a coordinated cellular response to RSS that parallels well-studied homeostatic stress responses like the unfolded protein response. By leveraging forward genetics and identifying new regulators of RSS, we propose to unveil a genetic framework for this novel type of cellular stress and provide new therapeutic inroads that exploit this cancer vulnerability.

三阴性乳腺癌（TNBC）是乳腺癌的一种侵袭性亚型，其发病率超过 每年新诊断20万例。癌基因 Myc 是 TNBC 的常见驱动因素。然而，尽管 尽管对 Myc 的生物学和分子功能进行了重要研究，但尚未出现可治疗的治疗方法 抑制这种致癌转录因子。 TNBC 和其他 Myc 驱动的癌症仍然顽固地抵抗当前的治疗 靶向治疗，强调迫切需要确定这些恶性肿瘤的新弱点。 除了促进肿瘤发生外，Myc 等癌基因还会在体内产生独特的应激 癌细胞，统称为致癌应激。使用平行全基因组 RNAi 筛选，我们发现 Myc 对 TNBC 施加一种新型致癌应激，我们称之为 RNA 剪接应激，或 RSS （凯斯勒，《科学》，2012 年；许，《自然》，2015 年）。在许多癌症类型中，Myc（或其他致癌损伤）在全球范围内 放大转录，导致剪接体上的前 mRNA 负担增加。因此，Myc 驱动的 TNBC 对剪接体中的适度扰动非常敏感（通过增强 RSS）。重要的是， 剪接体的药理学或遗传抑制剂会损害 TNBC 的原发性和转移性进展 在动物临床前模型中具有良好的耐受性。虽然剪接体抑制剂已进入临床试验， RSS 和剪接体抑制剂选择性杀死癌细胞的机制尚不清楚。在此，我们 提议发现感知和响应 RNA 剪接应力的途径并描绘 RSS 触发癌细胞死亡的机制。 目标 1：描绘体内 Myc+ TNBC 中 RSS 刺激的 dsRNA 传感通路 (DSP)。我们的 初步数据表明，RSS 通过触发检测 TNBC 的先天免疫途径来诱导 TNBC 细胞凋亡 并对 dsRNA 做出反应。通过利用具有新遗传和蛋白质组平台的 TNBC PDX 队列，我们​​将 确定 DSP 和其他应激反应途径如何响应剪接体抑制而被激活。 目标 2：了解 RSS 如何触发 TNBC 中的 dsRNA 传感通路。许多病毒病原体编码 由先天免疫系统的 dsRNA 传感器检测到的 dsRNA 基因组。我们的研究表明 RSS 导致内含子保留的 mRNA 在细胞质中积累，这是 dsRNA 的潜在来源。使用新的 测序和单分子显微镜方法，我们将研究RSS形成的机制 TNBC 转录组的二级结构和亚细胞定位并刺激 dsRNA 传感器。 目标 3：描述 DSP 和其他应激反应途径如何控制 TNBC 对 剪接体抑制剂。我们假设细胞对 RSS 存在协调反应，这与 经过充分研究的稳态应激反应，例如未折叠的蛋白质反应。通过利用正向遗传学 并确定了 RSS 的新调节因子，我们建议揭示这种新型细胞的遗传框架 压力并提供利用这种癌症脆弱性的新治疗方法。