A high-throughput drug combination screen of targeted small molecule inhibitors in cancer cell lines

Abstract While there is a high interest in drug combinations in cancer therapy, openly accessible datasets for drug combination responses are sparse. Here we present a dataset comprising 171 pairwise combinations of 19 individual drugs targeting signal transduction mechanisms across eight cancer cell lines, where the effect of each drug and drug combination is reported as cell viability assessed by metabolic activity. Drugs are chosen by their capacity to specifically interfere with well-known signal transduction mechanisms. Signalling processes targeted by the drugs include PI3K/AKT, NFkB, JAK/STAT, CTNNB1/TCF, and MAPK pathways. Drug combinations are classified as synergistic based on the Bliss independence synergy metrics. The data identifies combinations that synergistically reduce cancer cell viability and that can be of interest for further pre-clinical investigations.

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SYNERGxDB: an integrative pharmacogenomic portal to identify synergistic drug combinations for precision oncology

Nucleic Acids Research ◽

10.1093/nar/gkaa421 ◽

2020 ◽

Vol 48 (W1) ◽

pp. W494-W501 ◽

Cited By ~ 2

Author(s):

Heewon Seo ◽

Denis Tkachuk ◽

Chantal Ho ◽

Anthony Mammoliti ◽

Aria Rezaie ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Drug Combination ◽

Predictive Biomarkers ◽

Cancer Cell Lines ◽

Drug Combinations ◽

Drug Synergism ◽

Precision Oncology ◽

Synergistic Drug Combinations ◽

Pharmacological Profiles

Abstract Drug-combination data portals have recently been introduced to mine huge amounts of pharmacological data with the aim of improving current chemotherapy strategies. However, these portals have only been investigated for isolated datasets, and molecular profiles of cancer cell lines are lacking. Here we developed a cloud-based pharmacogenomics portal called SYNERGxDB (http://SYNERGxDB.ca/) that integrates multiple high-throughput drug-combination studies with molecular and pharmacological profiles of a large panel of cancer cell lines. This portal enables the identification of synergistic drug combinations through harmonization and unified computational analysis. We integrated nine of the largest drug combination datasets from both academic groups and pharmaceutical companies, resulting in 22 507 unique drug combinations (1977 unique compounds) screened against 151 cancer cell lines. This data compendium includes metabolomics, gene expression, copy number and mutation profiles of the cancer cell lines. In addition, SYNERGxDB provides analytical tools to discover effective therapeutic combinations and predictive biomarkers across cancer, including specific types. Combining molecular and pharmacological profiles, we systematically explored the large space of univariate predictors of drug synergism. SYNERGxDB constitutes a comprehensive resource that opens new avenues of research for exploring the mechanism of action for drug synergy with the potential of identifying new treatment strategies for cancer patients.

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Faculty Opinions recommendation of TIMMA-R: an R package for predicting synergistic multi-targeted drug combinations in cancer cell lines or patient-derived samples.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725335383.793503769 ◽

2015 ◽

Author(s):

Zdeněk Valenta

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

R Package ◽

Cancer Cell Lines ◽

Drug Combinations ◽

Targeted Drug

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Pharmaceutical immunoglobulin G impairs anti-carcinoma activity of oxaliplatin in colon cancer cells

British Journal of Cancer ◽

10.1038/s41416-021-01272-6 ◽

2021 ◽

Author(s):

Yuru Shang ◽

Xianbin Zhang ◽

Lili Lu ◽

Ke Jiang ◽

Mathias Krohn ◽

...

Keyword(s):

Colon Cancer ◽

Cell Viability ◽

Cancer Patients ◽

Cell Lines ◽

Cancer Cell ◽

Immunoglobulin G ◽

Cancer Cell Lines ◽

Human Igg ◽

Western Blots ◽

Igg Receptors

Abstract Background Recent evidence proves that intravenous human immunoglobulin G (IgG) can impair cancer cell viability. However, no study evaluated whether IgG application benefits cancer patients receiving chemotherapeutics. Methods Influence of pharmaceutical-grade human IgG on the viability of a series of patient-derived colon cancer cell lines with and without chemotherapeutic intervention was determined. Cell death was analysed flow cytometrically. In addition, the influence of oxaliplatin and IgG on the ERK1/2-signalling pathway was evaluated by western blots. Results We evaluated the effects of pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, in combination with chemotherapeutics. We did not observe any significant effects of IgG on tumour cell viability directly; however, human IgG significantly impaired the anti-tumoral effects of oxaliplatin. Primary cancer cell lines express IgG receptors and accumulate human IgG intracellularly. Moreover, while oxaliplatin induced the activation of ERK1/2, the pharmaceutical IgG inhibited ERK1/2 activity. Conclusions The present study demonstrates that pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, can impair the anti-carcinoma activity of oxaliplatin. These data strongly suggest that therapeutic IgG as co-medication might have harmful side effects in cancer patients. The clinical significance of these preclinical observations absolutely advises further preclinical, as well as epidemiological and clinical research.

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Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells

Cancers ◽

10.3390/cancers13153790 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3790

Author(s):

Gro Elise Rødland ◽

Sissel Hauge ◽

Grete Hasvold ◽

Lilli T. E. Bay ◽

Tine T. H. Raabe ◽

...

Keyword(s):

Lung Cancer ◽

Cell Viability ◽

Cancer Treatment ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Combined Treatment ◽

Cancer Cell Lines ◽

Variable Extent ◽

Synergistic Induction

Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR inhibitor VE822 were investigated in U2OS osteosarcoma cells and in four lung cancer cell lines, H460, A549, H1975, and SW900, with different sensitivities to the WEE1 inhibitor. Despite the differences in cytotoxic effects, the WEE1 inhibitor reduced the inhibitory phosphorylation of CDK, leading to increased CDK activity accompanied by ATR activation in all cell lines. However, combining ATR inhibition with WEE1 inhibition could not fully compensate for cell resistance to the WEE1 inhibitor and reduced cell viability to a variable extent. The decreased cell viability upon the combined treatment correlated with a synergistic induction of DNA damage in S-phase in U2OS cells but not in the lung cancer cells. Moreover, less synergy was found between ATR and WEE1 inhibitors upon co-treatment with radiation, suggesting that single inhibitors may be preferable together with radiotherapy. Altogether, our results support that combining WEE1 and ATR inhibitors may be beneficial for cancer treatment in some cases, but also highlight that the effects vary between cancer cell lines.

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