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

The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is lower than 8%. PDAC has the characteristics of high-density stroma and a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemo and immunotherapy. SUMOylation is a reversible post-translational modification required for cell cycle progression. We found that SUMOylation is increased in PDAC patient samples compared to primary pancreatic tissue. TAK-981, a novel highly selective and potent small molecule inhibitor of the SUMO activation enzyme E1 (SAE), selectively decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. In vivo TAK-981 efficiently limited the tumor burden in the KPC3 syngeneic mouse model without evidence of general toxicity. Interestingly, we found that TAK-981 modulates the immune system, up-regulating CD8+ T cells, NK cells and down-regulating B cells in peripheral blood, spleen, lymph nodes. Treatment of mouse primary T cells ex vivo with TAK-981 activated STAT1, the key transcription factor induced by interferon signaling. Our findings indicate that inhibition of the SUMO pathway might be a potential clinical strategy to target PDAC by inhibiting tumor cell division and activating anti-tumor immunity.

胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）的5年生存率不足8%。该肿瘤具有高密度间质与独特的免疫抑制微环境特征，对各类化疗与免疫治疗均具有极强的耐药性。SUMO化修饰（SUMOylation）是一类可逆的翻译后修饰，为细胞周期进程所必需。我们的研究发现，与正常胰腺组织相比，PDAC患者样本中的SUMO化修饰水平显著升高。TAK-981是一种新型高选择性、强效的SUMO激活酶E1（SUMO activation enzyme E1, SAE）小分子抑制剂，可在纳摩尔浓度范围内选择性降低PDAC细胞的SUMO化修饰水平，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异常。体内实验显示，TAK-981可在KPC3同基因小鼠模型中有效抑制肿瘤负荷，且未观察到明显的全身性毒性反应。有趣的是，我们还发现TAK-981可调节免疫系统：在外周血、脾脏与淋巴结中，该药物可上调CD8⁺ T细胞与自然杀伤（natural killer, NK）细胞，同时下调B细胞水平。通过离体处理小鼠原代T细胞，我们证实TAK-981可激活干扰素信号通路的关键转录因子STAT1。本研究结果表明，抑制SUMO通路或许是一种潜在的临床治疗策略，可通过阻滞肿瘤细胞分裂与激活抗肿瘤免疫来实现PDAC的靶向治疗。