The Bromodomain Inhibitor PFI-3 Sensitizes Cancer Cells to DNA Damage by Targeting SWI/SNF

Abstract

Many chemotherapeutic drugs produce double-strand breaks (DSB) 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 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 bromodomains 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 bromodomain inhibitor as a sensitizing agent in cancer chemotherapy.

Next‐generation bromodomain inhibitors of the SWI/SNF complex enhance DNA damage and cell death in glioblastoma

“…BRG1 promotes DNA strand breaks through nucleosome repositioning and altered recruitment of repair factors 39,40 . The BRG‐1/BRM inhibitor PFI‐3 exerts its DNA‐sensitising effects of doxorubicin in cancer cells by inhibiting DNA repair 41 . In contrast, the results described herein suggest that TEDs increase the amount of DNA breaks induced by TMZ and bleomycin.…”

SWI/SNF complex, promising target in melanoma therapy: Snapshot view

“…In general, and after reviewing various evidence that showed a contrast in the use of EZH2 inhibitors in cancers, especially mesothelioma, it seems that testing the response to EZH2 should be carefully evaluated before using these molecules as therapy ( 64 ). Recent research has shown that a novel bromodomain inhibitor called PFI-3, which targets SWI/SNF, and is responsible for repairing double-strand breaks in cancer, synergistically sensitizes many human cancers cell lines against DNA damage caused by chemotherapeutic agents such as doxorubicin ( 65 ). PFI-3 is a selective, potent, and cell-permeable SMARCA2/4 bromodomain inhibitor that has been previously characterized in the setting of various cancers (e.g., lung cancer, synovial sarcoma, leukemia, and rhabdoid tumors) ( 66 ).…”

3D chromatin architecture and transcription regulation in cancer

“…This study indicates mutations of SWI/SNF complex trigger carcinogenesis via inducing genome instability. Based on this hypothesis, a recently developed bromodomain inhibitor was proposed, targeting SWI/SNF complex to promote double-strand break and DNA repair [ 250 ], which demonstrates the feasibility for targeting SWI/SNF in cancer chemotherapy. Hong et al [ 251 ] reported carcinogenetic mechanisms of SMARCB1 and liver cancer.…”