The novel RNA polymerase I transcription inhibitor PMR-116 exploits a critical therapeutic vulnerability in a broad-spectrum of high MYC malignancies [ChIP-Seq]

Ribosome biogenesis (RiBi) is a key determinant of cell growth and proliferation and is highly elevated in cancer due to the activation by oncogenes such as MYC. First-generation RiBi inhibitor CX-5461, while demonstrating clinical potential for cancer treatment, also induces DNA damage through off-target inhibition of TOP2? and potentially other mechanisms, bringing into question RiBi as a target for cancer therapy. In this study, we test second-generation RiBi inhibitor, PMR-116. PMR-116 exhibits improved drug-like properties compared to first-generation RiBi inhibitors and has robust anti-tumour activity in the absence of global DNA damage signalling in a broad range of pre-clinical models of haematologic and solid cancers, particularly in malignancies where MYC is either the driver of disease or is elevated. Thus, our work demonstrates that RiBi is a genuine target for cancer therapy and highlights the potential to exploit a critical therapeutic vulnerability in high-MYC human cancers with dismal therapeutic outcomes. Overall design: ChIP-seq of Pol I and UBF in Mv4;11 and KG-1 acute myeloid leukemia (AML) cells which were treated with PMR-116 or vehicle control for 30 minutes.

核糖体生物发生（Ribosome biogenesis, RiBi）是细胞生长与增殖的关键决定因素，在癌症中因MYC等癌基因的激活而显著上调。第一代核糖体生物发生抑制剂CX-5461虽展现出癌症治疗的临床潜力，但可通过脱靶抑制TOP2及其他潜在机制诱发DNA损伤，这使得核糖体生物发生作为癌症治疗靶点的合理性受到质疑。本研究针对第二代核糖体生物发生抑制剂PMR-116开展测试。与第一代核糖体生物发生抑制剂相比，PMR-116具有更优异的成药性，且在广泛的血液系统与实体瘤临床前模型中，无需引发全局性DNA损伤信号即可展现出强效抗肿瘤活性，尤其在以MYC为疾病驱动因素或MYC高表达的恶性肿瘤中效果显著。综上，本研究证实核糖体生物发生是癌症治疗的真实有效靶点，并凸显了针对治疗预后极差的高MYC人类癌症开发靶向治疗策略的潜力。整体实验设计：对经PMR-116或溶剂对照处理30分钟的Mv4;11与KG-1急性髓系白血病（acute myeloid leukemia, AML）细胞开展RNA聚合酶I（RNA polymerase I, Pol I）与上游结合因子（Upstream Binding Factor, UBF）的染色质免疫共沉淀测序（ChIP-seq）。