BRCA1 E3 ligase inhibitors induces synthetic lethality in CPT resistant cells
Unan, Elizabeth Claire
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Camptothecin and its analogues (CPTs) represent one of the most potent classes of anticancer drugs used to treat several solid tumors. CPTs bind topoisomerase I during the replication process and cause DNA damage that results in cell death. However, its effectiveness is limited to 13-30 percent of patients. TopoI cuts and re-ligates DNA supercoiling but in the presence of CPT it fails to re-ligate DNA and collision of replication forks leads to DNA double strand break (DNA-DSB) and cell death. However, in resistant cells, due to deregulated kinase cascade, topoI is continually phosphorylated by DNA-PKcs and rapidly degraded by the ubiquitin proteasomal pathway (UPP). It has been found that BRCA1 plays a key role in imparting cellular resistance to topoI inhibitors. Importantly, BRCA1 ubiquitinates topoI in response to CPT. We hypothesize that disruption of BRCA1 binding to phosphorylated topoI would interrupt the resistance mechanism resulting in higher cellular sensitivity of CPT. Based on an in-silico drug screen, we identified a compound that inhibits topoI degradation by blocking BRCA1 binding. Imaging and survival assays findings are consistent with the hypothesis that BRCA1 plays a role in CPT resistance through its co-localization with topoI, and we speculate this role is through UPP degradation. CPTs are commonly used in combination with cytotoxic compounds, but this study focuses on discovering compounds that can overcome resistance without causing further cytotoxicity.