The bromodomain inhibitor PFI-3 sensitizes cancer cells to DNA damage by targeting SWI/SNF

Abstract

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.