Developing a genetic signature to predict drug response in ovarian cancer

Abstract

There is a lack of personalized treatment options for women with recurrent platinum-resistant ovarian cancer. Outside of bevacizumab and a group of poly ADP-ribose polymerase inhibitors, few options are available to women that relapse. We propose that efficacious drug combinations can be determined via molecular characterization of ovarian tumors along with pre-established pharmacogenomic profiles of repurposed compounds. To that end, we selectively performed multiple two-drug combination treatments in ovarian cancer cell lines that included reactive oxygen species inducers and HSP90 inhibitors. This allowed us to select cell lines that exhibit disparate phenotypes of proliferative inhibition to a specific drug combination of auranofin and AUY922. We profiled altered mechanistic responses from these agents in both reactive oxygen species and HSP90 pathways, as well as investigated PRKCI and lncRNA expression in ovarian cancer cell line models. Generation of dual multi-gene panels implicated in resistance or sensitivity to this drug combination was produced using RNA sequencing data and the validity of the resistant signature was examined using high-density RT-qPCR. Finally, data mining for the prevalence of these signatures in a large-scale clinical study alluded to the prevalence of resistant genes in ovarian tumor biology. Our results demonstrate that high-throughput viability screens paired with reliable in silico data can promote the discovery of effective, personalized therapeutic options for a currently untreatable disease.

Au2phen and Auoxo6, Two Dinuclear Oxo-Bridged Gold(III) Compounds, Induce Apoptotic Signaling in Human Ovarian A2780 Cancer Cells

“…Additionally, Trx has been found to activate the PI3K/AKT pathway [ 40 ], which in turn promotes cell proliferation, migration, and survival by phosphorylating and inactivating several key apoptotic molecules such as Bad, procaspase-9, and FKHR1(forkhead box protein 1) [ 51 ]. Recently, it was reported that auranofin alone or in combination with other drugs targeting TrxR can induce apoptosis through inhibition of the AKT pathway [ 29 , 52 , 53 , 54 , 55 ]. Similarly, the AKT pathway has been proven to take part in the apoptotic cell death induced by the auranofin-related compound chloro(triethylphosphine)gold(I) [ 56 ] and an N-heterocyclic carbene–gold(I) complex [ 57 ].…”

The gold complex auranofin: new perspectives for cancer therapy

“…Using a high-throughput viability screen and reliable in silico data allowed the rational identification of two pathways that can lead to synergistic interaction towards cell death in ovarian cancer. The study discovered that the TrxR inhibitor and ROS inducer auranofin synergized in the killing of ovarian cancer cells with the heat-shock protein 90 (HSP90) chaperone antagonist, AUY922 [ 112 ].…”

Upgrade of an old drug: Auranofin in innovative cancer therapies to overcome drug resistance and to increase drug effectiveness

“…Oommen et al demonstrated that in OVCAR5 and SKOV3 cells, BRCA1 silencing increased AF cytotoxicity and that AF‐induced DNA double strand brakes in a ROS‐dependent manner, thus demonstrating that BRCA1 deficiency renders tumor cells more sensitive to AF 112 . Hyter et al tested the cytotoxicity of AF alone or in combination with HSP90 inhibitors in ten ovarian cancer cell lines founding that there were remarkable differences in AF sensitivity in different lines 113 . They utilized A1847 and PEO4 as representative cell lines for the sensitive and resistant groups respectively and they demonstrated a synergic effect of AF and the HSP90 inhibitor AUY922.…”