Many chemotherapeutic drugs produce double-strand breaks (DSBs) on cancer cell DNA, thereby inducing cell death. However, the DNA damage response (DDR) enables cancer cells to overcome DNA damage and escape cell death, often leading to therapeutic resistance and unsuccessful outcomes. It is therefore important to develop inhibitors that target DDR proteins to render cancer cells hypersensitive to DNA damage. Here, we investigated the applicability of PFI-3, a recently developed bromodomain (BRD) inhibitor specifically targeting the SWI/SNF chromatin remodeler that functions to promote DSB repair, in cancer treatment. We verified that PFI-3 effectively blocks chromatin binding of its target BRDs and dissociates the corresponding SWI/SNF proteins from chromatin. We then found that, while having little toxicity as a single agent, PFI-3 synergistically sensitizes several human cancer cell lines to DNA damage induced by chemotherapeutic drugs such as doxorubicin. This PFI-3 activity occurs only for the cancer cells that require SWI/SNF for DNA repair. Our mechanism studies show that PFI-3 exerts the DNA damage-sensitizing effect by directly blocking SWI/SNF's chromatin binding, which leads to defects in DSB repair and aberrations in damage checkpoints, eventually resulting in increase of cell death primarily via necrosis and senescence. This work therefore demonstrates the activity of PFI-3 to sensitize cancer cells to DNA damage and its mechanism of action via SWI/SNF targeting, providing an experimental rationale for developing PFI-3 as a sensitizing agent in cancer chemotherapy. Implications: This study, revealing the activity of PFI-3 to sensitize cancer cells to chemotherapeutic drugs, provides an experimental rationale for developing this BRD inhibitor as a sensitizing agent in cancer chemotherapy.

中文翻译：

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溴结构域抑制剂 PFI-3 通过靶向 SWI/SNF 使癌细胞对 DNA 损伤敏感

许多化疗药物在癌细胞 DNA 上产生双链断裂 (DSB)，从而诱导细胞死亡。然而，DNA 损伤反应 (DDR) 使癌细胞能够克服 DNA 损伤并避免细胞死亡，这通常会导致治疗耐药和不成功的结果。因此，重要的是开发靶向 DDR 蛋白的抑制剂，以使癌细胞对 DNA 损伤过敏。在这里，我们研究了 PFI-3 的适用性，这是一种最近开发的溴结构域 (BRD) 抑制剂，专门针对 SWI/SNF 染色质重塑剂，可促进 DSB 修复，用于癌症治疗。我们验证了 PFI-3 有效地阻断了其靶 BRD 的染色质结合，并将相应的 SWI/SNF 蛋白从染色质中解离出来。然后我们发现，虽然作为单一药剂毒性很小，PFI-3 协同作用地使几种人类癌细胞系对阿霉素等化疗药物诱导的 DNA 损伤敏感。这种 PFI-3 活性仅发生在需要 SWI/SNF 进行 DNA 修复的癌细胞中。我们的机制研究表明，PFI-3通过直接阻断SWI/SNF的染色质结合发挥DNA损伤致敏作用，导致DSB修复缺陷和损伤检查点异常，最终导致主要通过坏死和衰老的细胞死亡增加。因此，这项工作证明了 PFI-3 使癌细胞对 DNA 损伤敏感的活性及其通过 SWI/SNF 靶向的作用机制，为开发 PFI-3 作为癌症化疗中的致敏剂提供了实验原理。启示：这项研究，