PG545（Pixatimod）是一种高度硫酸化的小分子，以其抑制肝素酶（heparanase）和破坏肝素结合生长因子（heparan-binding-growth factors，HB-GF）介导的信号传导能力而闻名。之前的研究表明，PG545能够抑制卵巢癌（OC）中的生长因子介导的信号传导，增强化疗的响应。在这里，我们研究了PG545在OC细胞中引起DNA损伤的前期未知机制，并发现PG545能够诱导DNA单链断裂和双链断裂，以一种自噬依赖的方式降低RAD51的表达，并抑制同源重组修复（HRR）。这些变化伴随着PG545抑制肝素硫酸蛋白聚糖相互作用DNA修复蛋白DEK的内吞作用，导致DEK在肿瘤微环境（TME）中被隔离，并失去核内对HRR所需的DEK。因此，PG545与多聚（ADP核糖）聚合酶抑制剂（PARPis）在OC细胞系体外和55%原发性培养的患者腹水样本体外表现出协同作用。此外，PG545与鲁卡帕尼（rucaparib）的协同作用也在体内展示出增加的DNA损伤、增加的抗肿瘤效果以及增加携带HRR能力的OVCAR5异种移植瘤小鼠的存活率，与单药治疗相比。PG545/鲁卡帕尼的组合也在免疫能力正常的同种移植ID8F3 OC模型中观察到协同的抗肿瘤活性。总的来说，这些结果表明，通过使用PG545靶向DEK-HSPG在TME的相互作用可能是一种抑制DNA修复并使细胞对PARPis敏感的新方法。©2023. 作者。

PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors (HB-GF). Previous studies indicated that PG545 inhibits growth factor-mediated signaling in ovarian cancer (OC) to enhance response to chemotherapy. Here we investigated the previously unidentified mechanisms by which PG545 induces DNA damage in OC cells and found that PG545 induces DNA single- and double-strand breaks, reduces RAD51 expression in an autophagy-dependent manner and inhibits homologous recombination repair (HRR). These changes accompanied the ability of PG545 to inhibit endocytosis of the heparan-sulfate proteoglycan interacting DNA repair protein, DEK, leading to DEK sequestration in the tumor microenvironment (TME) and loss of nuclear DEK needed for HRR. As a result, PG545 synergized with poly (ADP-ribose) polymerase inhibitors (PARPis) in OC cell lines in vitro and in 55% of primary cultures of patient-derived ascites samples ex vivo. Moreover, PG545/PARPi synergy was observed in OC cells exhibiting either de novo or acquired resistance to PARPi monotherapy. PG545 in combination with rucaparib also generated increased DNA damage, increased antitumor effects and increased survival of mice bearing HRR proficient OVCAR5 xenografts compared to monotherapy treatment in vivo. Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis.© 2023. The Author(s).