Synthetic lethal combinations of low-toxicity drugs for breast cancer identified in silico by genetic screens in yeast
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Maximilian Marhold1, Erwin Tomasich1, Michael Schwarz2, Simon Udovica2, Andreas Heinzel3, Paul Mayer3, Peter Horak4, Paul Perco3 and Michael Krainer1
1Department for Internal Medicine I–Oncology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
2Clinic of Internal Medicine I, Wilhelminenspital Wien, Vienna, Austria
3Emergentec biodevelopment, Vienna, Austria
4Department for Translational Oncology, German Cancer Research Institute (DKFZ), Heidelberg, Germany
Michael Krainer, email: [email protected]
Keywords: synthetic lethality; breast cancer; drug combination; cancer; treatment
Received: February 14, 2017 Accepted: October 21, 2018 Published: November 20, 2018
In recent years, the concept of synthetic lethality, describing a cellular state where loss of two genes leads to a non-viable phenotype while loss of one gene can be compensated, has emerged as a novel strategy for cancer therapy. Various compounds targeting synthetic lethal pathways are either under clinical investigation or are already routinely used in multiple cancer entities such as breast cancer. Most of them target the well-described synthetic lethal interplay between PARP1 and BRCA1/2. In our study, we investigated, using an in silico methodological approach, clinically utilized drug combinations for breast cancer treatment, by correlating their known molecular targets with known homologous interaction partners that cause synthetic lethality in yeast. Further, by creating a machine-learning algorithm, we were able to suggest novel synthetic lethal drug combinations of low-toxicity drugs in breast cancer and showed their negative effects on cancer cell viability in vitro. Our findings foster the understanding of evolutionarily conserved synthetic lethality in breast cancer cells and might lead to new drug combinations with favorable toxicity profile in this entity.
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