PO.CL06.03 · 临床研究

劫持BRD4-NUT融合癌蛋白以激活程序性细胞死亡

Hijacking the BRD4-NUT fusion oncoprotein to activate programmed cell death

编号 7881 展板 12 时间 4/22 09:00–12:00 区域 Section 47 主讲 Kelly Wang, No Degree

分会场 Targeted Therapies, Predispositions, and Survivorship in Pediatric Cancers

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作者与单位 Authors & Affiliations

Kelly Wang¹, Yanlan Wang¹, Tian Qiu², Brendan G. Dwyer², Daryl Griffin³, Geoffrey I. Shapiro³, Chris A. French⁴, Nathanael S. Gray², Gerald R. Crabtree¹

¹Dept. of Pathology and Developmental Biology, Stanford University, Stanford, CA,²Dept. of Chemical and Systems Biology, Stanford University, Stanford, CA,³Dept. of Medical Oncology and Medicine, Dana-Farber Cancer Institute, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,⁴Professor, Dept. of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA

摘要 Abstract

中文摘要

融合癌基因约占所有癌症驱动因素的10-20%，通常由与特定伙伴基因的框内重组产生。由融合癌基因驱动的癌症常发生于基因组相对没有其他突变的年轻人群，从而形成对该融合基因及其潜在机制的单一依赖。尽管有此聚焦点，融合癌基因——尤其是源自转录因子的融合癌基因——在治疗上一直难以靶向。本研究证明，融合癌蛋白BRD4-NUT可用于在一种侵袭性鳞状癌——NUT癌（NC）中特异性激活程序性细胞死亡。NC由NUTM1基因易位至BRD4基因下游引起。因此，融合基因的转录受BRD4调控区控制，导致融合癌蛋白的高水平表达。NUT蛋白正常情况下仅限于睾丸表达，在那里它对组蛋白的高度乙酰化、组蛋白的去除及被鱼精蛋白替换至关重要。NC目前的平均生存期为6-9个月，且无获批治疗方案。我们推断BRD4-NUT的致癌程序可被重新编程以激活一个合成的死亡回路。为选择性抑制NC，我们开发了靶向BRD4-NUT融合蛋白、BRD4及PARP的双功能分子。我们将这类新型分子命名为DD-CIP，即DNA损伤-化学邻近诱导剂（DNA Damage-Chemical Inducers of Proximity）。该新型分子中效力最强的成员（TWQ-184）在0.74 nM至6 nM的浓度下杀死NC细胞系（10-15、SW和14169）。TWQ-184与BRD4-NUT和PARP形成三元复合物，导致细胞死亡。P300抑制剂可部分挽救NC细胞免于TWQ-184诱导的凋亡，提示由BRD4-NUT驱动的、在PARP结合的DNA断裂处进行的转录是启动细胞死亡所必需的。TWQ-184在24小时内诱导gammaH2AX沉积和ATM激活，提示PARP结合的单链断裂被转化为致死性的双链断裂。暴露于TWQ-184一小时后，在72小时时可实现近乎完全的NC细胞死亡，提示间歇给药可能有效。TWQ-184还对恶性细胞表现出高度特异性，NC细胞系与健康人类淋巴细胞及成纤维细胞之间存在显著的治疗窗口即为佐证。基于我们目前的发现，该化合物在癌细胞中的高疗效及在健康细胞中的低毒性，为治疗NC提供了一种有前景的方法。这种劫持融合癌蛋白以激活转录偶联的DNA损伤介导的细胞死亡的策略，可能适用于其他转录性融合癌基因。

查看英文原文 English abstract

Fusion oncogenes account for about 10-20% of all cancer drivers and generally result from in-frame recombination with specific partners. Cancers driven by fusion oncogenes often occur in young people whose genomes are relatively free of other mutations, providing a singular reliance on the fusion and its underlying mechanisms. Despite this focus, fusion oncogenes - particularly those that arise from transcription factors - have been difficult to target therapeutically. We demonstrate in this study that the fusion oncoprotein BRD4-NUT can be used to specifically activate programmed cell death in an aggressive form of squamous cancer, NUT carcinoma (NC). NC is caused by a translocation of the NUTM1 gene downstream of the BRD4 gene. Transcription of the fusion gene is therefore controlled by the BRD4 regulatory region, leading to high-level expression of the fusion oncoprotein. The NUT protein is normally restricted to the testes, where it is essential for histone hyperacetylation, histone removal and replacement by protamines. NC currently has a mean‬‭ survival of 6-9 months and no approved treatments. We reasoned that the oncogenic program of BRD4-NUT could be reprogrammed to activate a synthetic death circuit. To selectively inhibit NC, we developed bifunctional molecules that target the BRD4-NUT fusion, BRD4 and PARP. We call the new class of molecules DD-CIPs for DNA Damage-Chemical Inducers of Proximity. The most potent member of this new class (TWQ-184) kills NC cell lines (10-15, SW and 14169) at concentrations between 0.74 nM and 6 nM. TWQ-184 forms a ternary complex with BRD4-NUT and PARP, resulting in cell death. P300 inhibitors partially rescue NC cells from TWQ-184-induced apoptosis, suggesting that transcription at PARP-bound DNA breaks driven by BRD4-NUT is required to initiate cell death. TWQ-184 induces gammaH2AX deposition and ATM activation within 24 hours, suggesting that PARP-bound single-strand breaks are converted to lethal double-strand breaks in the cancer cells. Exposure to TWQ-184 for one hour gives near-complete NC death at 72 hours, suggesting that intermittent dosing might be effective. TWQ-184 additionally exhibits high specificity for the malignant cells, evidenced by the substantial therapeutic windows between NC cell lines and healthy human lymphocytes and fibroblasts. Based on our current findings, the compound's high efficacy in the cancer cells and low toxicity in healthy cells offer a promising approach to treat NC. This strategy for hijacking a fusion oncoprotein to activate transcriptionally coupled DNA damage-mediated cell death could be applicable to other transcriptional fusion oncogenes.‬‬‬

利益披露 Disclosure

K. Wang, None.. Y. Wang, None.. T. Qiu, None.. B. G. Dwyer, None.. D. Griffin, None. G. I. Shapiro, Merck KGaA/EMD-Serono ). Artios ). Lilly ). Pfizer ). Dosage regimen for sapacitabine and seliciclib Patent. Compositions and Methods for Predicting Response and Resistance to CDK4/6 inhibition Patent. Merck KGaA/EMD-Serono Other, Scientific Advisory Board. Circle Pharmaceuticals Other, Scientific Advisory Board. Concarlo Therapeutics Other, Scientific Advisory Board. Schrodinger Scientific Advisory Board. FoRx Therapeutics Scientific Advisory Board. MycRx Scientific Advisory Board. C. A. French, None. N. S. Gray, Syros Other, Scientific Advisory Board. Allorion Other, Scientific Advisory Board. Lighthorse Other, Scientific Advisory Board. Voronoi Other, Scientific Advisory Board. Inception Other, Scientific Advisory Board. Matchpoint Other, Scientific Advisory Board. CobroVentures Other, Scientific Advisory Board. GSK Other, Scientific Advisory Board. Shenandoah Therapeutics g., Board of Directors, non-salaried role), Other, Scientific Advisory Board. Larkspur g., Board of Directors, non-salaried role), Other, Scientific Advisory Board. Soltego g., Board of Directors, non-salaried role), Other, Scientific Advisory Board. Novartis ). Takeda ). Astellas ). Taiho ). Jansen ). Kinogen ). Arbella ). Deerfield ). Springworks ). G. R. Crabtree, Foghorn Therapeutics g., Board of Directors, non-salaried role). Shenandoah Therapeutics g., Board of Directors, non-salaried role).

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