Targeting Pancreatic Cancer by TAK-981, a SUMOylation Inhibitor that Activates the Immune System and Blocks Cancer Cell Cycle Progression in a Preclinical Model

Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC. We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activating enzyme E1 (SAE) could be used to treat a preclinical syngeneic PDAC mouse model. We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared to normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumor burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and NK cells but transiently decreased B cell numbers in peripheral blood, spleen and lymph nodes. ScRNA sequencing revealed activation of the interferon response upon TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes. Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumor immunity by inducing interferon signaling. Overall design: Identify genes in response to SUMO inhibition in lymph nodes and spleen

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）具有高密度促结缔组织增生基质、独特的免疫抑制微环境特征，且对所有化疗与免疫治疗方案均具有显著抗性，5年生存率仅为9%。本研究旨在为胰腺导管腺癌的治疗开发新型小分子治疗药物。我们探究了TAK-981——一种新型高选择性、强效的SUMO激活酶E1（SUMO activating enzyme E1, SAE）小分子抑制剂——是否可用于治疗临床前同源基因胰腺导管腺癌小鼠模型。我们发现，相较于正常胰腺组织，类泛素化修饰（SUMOylation）——一种调控细胞周期进程的可逆性翻译后修饰——在胰腺导管腺癌患者样本中表达上调。TAK-981可在纳摩尔浓度范围内抑制胰腺导管腺癌细胞的类泛素化修饰，进而引发G2/M期细胞周期阻滞、有丝分裂失败及染色体分离缺陷。TAK-981可有效降低KPC3同源基因小鼠模型的肿瘤负荷，且未观察到全身毒性反应。体内TAK-981治疗可提升外周血、脾脏及淋巴结中活化CD8阳性T细胞与自然杀伤细胞（NK细胞）的比例，但会暂时性减少B细胞数量。单细胞RNA测序（scRNA-seq）结果显示，TAK-981处理后，T、B及NK细胞等淋巴细胞内的干扰素应答通路被激活。体外实验中，TAK-981处理CD8阳性T细胞可诱导信号转导与转录激活因子1（STAT1）及干扰素靶基因的活化。本研究结果表明，对SUMO通路进行药理学抑制有望通过双重机制靶向治疗胰腺导管腺癌：一是抑制癌细胞周期进程，二是通过诱导干扰素信号通路激活抗肿瘤免疫。整体实验设计：筛选淋巴结与脾脏中响应SUMO抑制的基因。