Combinatorial drug therapy for cancer in the post-genomic era

Al‐Lazikani, Bissan; Banerji, Udai; Workman, Paul

doi:10.1038/nbt.2284

Cited by 866 publications

(724 citation statements)

References 160 publications

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“…Besides the development of new therapeutic approaches, one of the most promising options to improve treatment efficacy is the use of combination strategies (39). The anticancer activity of arsenic is well known and resulted in the recent approval of ATO against APL (1).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Kryeziu

Jungwirth

Hoda

et al. 2013

Molecular Cancer Therapeutics

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Arsenic trioxide (ATO), one of the oldest remedies used in traditional medicine, was recently rediscovered as an anticancer drug and approved for treatment of relapsed acute promyelocytic leukemia. However, its activity against nonhematologic cancers is rather limited so far. Here, we show that inhibition of ATO-mediated EGF receptor (EGFR) activation can be used to potently sensitize diverse solid cancer types against ATO. Thus, combination of ATO and the EGFR inhibitor erlotinib exerted synergistic activity against multiple cancer cell lines. Subsequent analyses revealed that this effect was based on the blockade of ATO-induced EGFR phosphorylation leading to more pronounced G 2 -M arrest as well as enhanced and more rapid induction of apoptosis. Comparable ATO-sensitizing effects were also found with PI3K/AKT and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, suggesting an essential role of the EGFRmediated downstream signaling pathway in cancer cell protection against ATO. H2AX staining and comet assay revealed that erlotinib significantly increases ATO-induced DNA double-strand breaks (DSB) well in accordance with a role of the EGFR signaling axis in DNA damage repair. Indeed, EGFR inhibition led to downregulation of several DNA DSB repair proteins such as Rad51 and Rad50 as well as reduced phosphorylation of BRCA1. Finally, the combination treatment of ATO and erlotinib was also distinctly superior to both monotreatments against the notoriously therapy-resistant human A549 lung cancer and the orthotopic p31 mesothelioma xenograft model in vivo. In conclusion, this study suggests that combination of ATO and EGFR inhibitors is a promising therapeutic strategy against various solid tumors harboring wild-type EGFR. Mol Cancer Ther; 12(6); 1073-84. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Kryeziu

Jungwirth

Hoda

et al. 2013

Molecular Cancer Therapeutics

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“…There was no significant difference (Chi-sqr P=0.44) in OmniPath protein network distance between targets of well and poorly predicted combinations ( Figure 4D). 5. Algorithms from top performing teams generalize to an independent drug screening data set.…”

Section: Increasing Performance Using Biologically Meaningful Featuresmentioning

confidence: 99%

“…This is further complicated by the necessity to consider multiple phenotypic endpoints and disease and cellular contexts, rendering it impractical to cover all possibilities with experimental screens 4 . Computational approaches for predicting drug synergy are critical to guide experimental approaches for discovery of rational combination therapy 5 .…”

Section: Introductionmentioning

confidence: 99%

A cancer pharmacogenomic screen powering crowd-sourced advancement of drug combination prediction

Wang

Guan

et al. 2017

Preprint

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In the last decade advances in genomics, uptake of targeted therapies, and the advent of personalized treatments have fueled a dramatic change in cancer care. However, the effectiveness of most targeted therapies is short lived, as tumors evolve and develop resistance. Combinations of drugs offer the potential to overcome resistance. The space of possible combinations is vast, and significant advances are required to effectively find optimal treatment regimens tailored to a patient's tumor. DREAM and AstraZeneca hosted a Challenge open to the scientific community aimed at computational prediction of synergistic drug combinations and predictive biomarkers associated to these combinations. We released a data set comprising ~11,500 experimentally tested drug combinations, coupled to deep molecular characterization of the respective 85 cancer cell lines. Among 150 submitted approaches, those that incorporated prior knowledge of putative drug targets showed superior performance predicting drug synergy across independent data. Genomic features of best-performing models revealed putative mechanisms of drug synergy for multiple drugs in combination with PI3K/AKT pathway inhibitors.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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“…It is suggested that different tumor cell types have their own unique mechanisms leading to MDR (Gillet and Gottesman, 2010;Al-Lazikani et al, 2012). The association between GST and tumors was initially reported by Wang (Wang and Few, 1985).…”

Section: Discussionmentioning

confidence: 97%