Synthetic Lethal Drug Combinations Targeting Proteasome and Histone Deacetylase Inhibitors in TP53-Mutated Cancers.

Background: We have recently published SL-BioDP, a web resource for querying, exploration and visualization of potential synthetic lethal targets and possible synergistic drug combinations for 18 cancer types.

Methods: From our predictive synthetic lethality model used in SL-BioDP, we inferred TP53 mutation lead to potential synergistic drug combination of Bortezomib and Vorinostat. Here we show, how to extrapolate the drug combination results by combining drug screening data from cancer cell lines and showed the potential synergy of the drug targets, proteasome, and histone deacetylase (HDAC) pathways respectively, for patient survival advantage.

Results: We found that TP53 mutation is potentially synthetic lethal with multiple genes from the proteasome and HDAC pathways exclusively in many cancer types. Also, HDAC and proteasomes were found to have potential synthetic lethal relationship. Using drug screening data in cancer cell line, the sensitivity of the HDAC inhibitor drug Vorinostat was found to be increased in TP53 mutated cells where the proteasome pathway was downregulated.

Conclusions: Our in-silico pharmacogenomic study indicates that the potential synergistic drug combination of proteasome and HDAC inhibitors may be considered as potential treatment for TP53-mutant cancers.