This study is led by Prof. Mingyu Chen (Sir Run-Run Shaw Hospital, Zhejiang University), Prof. Xiujun Cai (Sir Run-Run Shaw Hospital, Zhejiang University), Prof. Jicheng Yu (College of Pharmaceutical Sciences, Zhejiang University), Dr. Shjie Li (Sir Run-Run Shaw Hospital, Zhejiang University), Dr. Sarun Juengpanich (Sir Run-Run Shaw Hospital, Zhejiang University) and Dr. Win Topatana (Sir Run-Run Shaw Hospital, Zhejiang University).
Since the revelation of poly(ADP-ribose) polymerase (PARP) inhibitors and their remarkable results in the treatment of BRCA1/2 mutant cancers, synthetic lethality (SL) in antitumor therapy has attracted increasing attention. SL is a phenomenon wherein a single genetic event is insufficient to induce cell death, but multiple genetic events lead to cell death. The characterization of SL genetic interactions with tumor-specific mutations can be used to develop a conceptual framework for tackling "undruggable" targets such as tumor suppressor gene p53. Gallbladder cancer (GBC) is the most prevalent malignant tumor of the biliary system and is typically fatal due to the limited efficacy of existing treatment. It has been reported that p53 is one of the most frequently mutated genes and a poor prognostic marker in GBC. Therefore, SL-based strategy for targeting p53-mutated GBC is a promising approach.
Studies have shown that DNA damage repair achieved by WEE1 through the regulation of cell cycle G2 checkpoint is essential for the survival of p53-mutated cells. Therefore, adavosertib (ADA), a WEE1 inhibitor, has a significant synthetic lethal effect on p53-mutated cancers. However, drug resistance due to DNA damage response (DDR) compensation pathways and high toxicity limits further applications. Recent studies indicated that the use of physical factors such as photodynamic therapy (PDT), sonodynamic therapy (SDT), and gas therapy in the treatment of tumors has superior effects and a broader range of applications than conventional chemical drugs. Physical factors provide irreversible conditions to enhance the synthetic lethal effect of tumor-killing will prove to be an effective strategy.
