Synthetic lethality guiding selection of drug combinations in ovarian cancer.

Andreas Heinzel,Arno Lukas,Michael Krainer,Michael Schwarz,Paul Perco,Erwin Tomasich,Maximilian Marhold,Paul Mayer,Aamir Ahmad

doi:10.1371/journal.pone.0210859

Abstract

BackgroundSynthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy.Materials and methodsWe established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.ResultsTwelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies.ConclusionA set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.

Highlights

The concept of synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality [1][2]
In summary we on the one hand could show that drug combinations currently in late stage clinical testing address synthetic lethal interactions and on the other hand we identified a set of drug combinations currently not tested in late stage ovarian cancer clinical trials worth of further investigation due to their impact on synthetic lethal interactions
Complete list of synlet interactions addressed by novel drug combinations

Summary

Introduction

The concept of synthetic lethality (synlet) describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality [1][2]. One option is to address a tumor bearing a non-functional protein (either via mutation or downregulation) with a drug targeting a gene product being in a synthetic lethal interaction with the non-functional gene product [4]. Such approach promises improving safety in case the drug is not addressing a vital target mechanism. Another option is to use drug combinations where each drug is targeting a tumor-specific entity which in combination are synthetic lethal [5]. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy

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Results

Conclusion