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

Shaoli Das,Xiang Yun Deng ,Kevin Camphausen,Uma Shankavaram

doi:10.33696/cancerbiology.1.009

Abstract

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. 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. 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. 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.

Highlights

Tumors harboring mutations in certain oncogenes are often dependent on activation of certain pathways which becomes essential for the survival of the cancer cells
Using our SL prediction algorithm combined with cancer patient survival analysis from The Cancer Genome Atlas (TCGA) clinical data and insilico drug sensitivity analysis from cancer cell lines, we show results supporting the idea that the combination of the drugs Bortezomib and Vorinostat might be beneficial for treating TP53-mutated cancers
Multiple genes from the histone deacetylase (HDAC) pathways were shortlisted as potential SL partners for TP53 mutation, e.g. HDAC8 in breast cancer (BRCA), HDAC5, HDAC6 and HDAC7 in bladder cancer (BLCA), HDAC2 and HDAC6 in lower grade glioma (LGG), HDAC4 in lung adenocarcinoma (LUAD)

Summary

Introduction

Tumors harboring mutations in certain oncogenes are often dependent on activation of certain pathways which becomes essential for the survival of the cancer cells This condition is formally known as synthetic lethality, a state when simultaneous loss of two genes is lethal to a cancer cell, while the loss of the individual genes is not. These alternative genes or pathways are of potential interest as drug targets, which makes it possible to uniquely target tumor cells harboring oncogenic mutations [1]. 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

Results

Conclusion