Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 14 (1), e0210859
eCollection

Synthetic Lethality Guiding Selection of Drug Combinations in Ovarian Cancer

Affiliations

Synthetic Lethality Guiding Selection of Drug Combinations in Ovarian Cancer

Andreas Heinzel et al. PLoS One.

Abstract

Background: 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. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy.

Materials and methods: We 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.

Results: Twelve 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.

Conclusion: A 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.

Conflict of interest statement

AL is managing partner of emergentec biodevelopment GmbH, Austria. AH, PP, and PM at the time of performing the analysis were employees of emergentec biodevelopment GmbH. Commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. All authors declare that they have no competing interests.

Figures

Fig 1
Fig 1. Ovarian cancer clinical trial workflow.
Fig 1 depicts an overview on the search strategy to identify relevant ovarian cancer clinical trials and drug combinations along with numbers of the individual processing steps.
Fig 2
Fig 2. Drug-drug combination map.
Fig 2 depicts the pairwise drug-drug combinations extracted from phase III and IV ovarian cancer clinical trials of the 43 drugs used in these combinations. The edge width corresponds to the number of the studied drug-drug combination with combinations already used in the clinical setting indicated by a red edge. Drugs having at least one protein target assigned have a grey background, whereas drugs not directly targeting specific proteins but merely interfering with DNA are displayed with a white background.
Fig 3
Fig 3. Synlet map of known drug combinations.
Fig 3 depicts synlet pairs addressed by drug combinations either already approved or in late stage clinical testing. Color-coded number tags indicate the twelve pairwise drug combinations. Synlet edges are displayed in red with drug target links shown in grey color. The width of synlet edges corresponds to the number of trials available testing drug combinations addressing the respective synlet interaction.
Fig 4
Fig 4. Synlet map of novel proposed drug combinations.
Fig 4. depicts synlet pairs being eligible to be addressed by drug combinations currently not in clinical use or late stage clinical testing. Each two drugs targeting the two synlet partners can be considered as drug combination. Synlet edges are displayed in red with drug target links shown in grey color. The width of synlet edges corresponds to the number of drug combinations targeting this specific synlet interaction. Synlet interactions already addressed by drug combinations in clinical use or late stage testing are indicated by dotted lines. These drug combinations are composed of those drugs flagged with an asterisk (*) each in combination with paclitaxel always via the path through the dotted synlet interaction or with a circle (o) for the combination between cediranib and olaparib.

Similar articles

See all similar articles

Cited by 2 articles

References

    1. Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH. Integrating genetic approaches into the discovery of anticancer drugs. Science. 1997;278: 1064–8. - PubMed
    1. Nijman SMB. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett. 2011;585: 1–6. 10.1016/j.febslet.2010.11.024 - DOI - PMC - PubMed
    1. Dobzhansky T. Genetics of Natural Populations. Xiii. Recombination and Variability in Populations of Drosophila Pseudoobscura. Genetics. 1946;31: 269–90. - PMC - PubMed
    1. Fechete R, Barth S, Olender T, Munteanu A, Bernthaler A, Inger A, et al. Synthetic lethal hubs associated with vincristine resistant neuroblastoma. Mol Biosyst. 2011;7: 200–14. 10.1039/c0mb00082e - DOI - PubMed
    1. Hijaz M, Chhina J, Mert I, Taylor M, Dar S, Al-Wahab Z, et al. Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer. Gynecol Oncol. 2016;142: 323–31. 10.1016/j.ygyno.2016.06.005 - DOI - PubMed

Publication types

MeSH terms

Grant support

The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement no. 279113 (OCTIPS).
Feedback