Drug-based perturbation screen uncovers synergistic drug combinations in Burkitt lymphoma

Tomska, Katarzyna; Kurilov, Roman; Lee, Kwang Seok; Hüllein, Jennifer; Lukas, Marina; Sellner, Leopold; Walther, Tatjana; Wagner, Lena; Oleś, Małgorzata; Brors, Benedikt; Huber, Wolfgang; Zenz, Thorsten

doi:10.1038/s41598-018-30509-3

Cited by 26 publications

(20 citation statements)

References 62 publications

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“…1). In line with procedures applied by other drug screen labs 5,6,13,14 , we used viability as assessed by ATP content (CellTiter-Glo) as the main readout to gauge drug responses in 2D and 3D cultures. Additional readouts included measurement of confluency (2D), spheroid diameter (3D) and cell death (2D).…”

Section: Resultsmentioning

confidence: 99%

High-throughput screening reveals higher synergistic effect of MEK inhibitor combinations in colon cancer spheroids

Folkesson

Niederdorfer

Nakstad

et al. 2020

Sci Rep

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Drug combinations have been proposed to combat drug resistance, but putative treatments are challenged by low bench-to-bed translational efficiency. To explore the effect of cell culture format and readout methods on identification of synergistic drug combinations in vitro, we studied response to 21 clinically relevant drug combinations in standard planar (2D) layouts and physiologically more relevant spheroid (3D) cultures of HCT-116, HT-29 and SW-620 cells. By assessing changes in viability, confluency and spheroid size, we were able to identify readout-and culture format-independent synergies, as well as synergies specific to either culture format or readout method. In particular, we found that spheroids, compared to 2D cultures, were generally both more sensitive and showed greater synergistic response to combinations involving a MEK inhibitor. These results further shed light on the importance of including more complex culture models in order to increase the efficiency of drug discovery pipelines. Colorectal cancer (CRC) is the third most common neoplastic malignancy worldwide 1 , and although improvements in standard treatments have increased the survival rates over the past 20 years 2 , far from all patients benefit from currently available therapies. Targeted therapy, using drugs aimed to target specific molecules involved in tumour growth, is being regarded as a promising tool to increase response rates to cancer therapy. However, the number of such therapies that have made it all the way to the clinic has been limited. This may be explained by lack of therapy response due to adaptive drug resistance, or transient response due to acquired resistance. Drug combinations are being discussed as a promising strategy to overcome the resistance frequently observed upon administration of targeted monotherapy 3,4. The augmented effect of targeted drug combination treatment is frequently ascribed to the drugs' ability to jointly interfere with the growth-promoting signalling network of cancer cells at multiple points. High-throughput cell line screening platforms have been successfully employed as tools to uncover novel synergistic drug combinations. In the study ALMANAC of the National Cancer Institute (NCI), where a large number of pairwise combinations of FDA-approved cancer drugs were screened in vitro, several novel pairs of synergistic drug combinations were identified, whereof roughly a third also were shown to be efficient and synergistic in vivo 5. Another example is the Merck Research Laboratories screen, in which 583 combinations of experimental and approved cancer drugs were screened in a panel of cancer cell lines, identifying well-known as well as novel synergistic drug combinations in vitro 6. Despite large combination screening efforts with successful hits in vitro, putative treatments are challenged by low bench-to-bed translational efficiency. The insufficient ability of cell lines grown on planar surfaces to correctly recapitulate drug response in vivo has been debated as a possible explanation ...

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Section: Resultsmentioning

confidence: 99%

High-throughput screening reveals higher synergistic effect of MEK inhibitor combinations in colon cancer spheroids

Folkesson

Niederdorfer

Nakstad

et al. 2020

Sci Rep

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“…Interestingly, the Raji cell line was resistant to the MB-3 inhibitor. Previous studies indicate that this cell line is drug insensitive, particularly to inhibitors of the PI3K and BCR pathways [51, 52]. Overall, GCN5 HAT inhibition disrupts BCR signaling and reduces phosphorylation of key effectors, thereby reducing viability and inducing apoptosis in Burkitt lymphoma cells.…”

Section: Discussionmentioning

confidence: 89%

GCN5 HAT inhibition reduces human Burkitt lymphoma cell survival through reduction of MYC target gene expression and impeding BCR signaling pathways

et al. 2019

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GCN5, the catalytic subunit in the acetyltransferase modules of SAGA and ATAC, functions as a coactivator of gene transcription. The SAGA complex is recruited to chromatin by transcription factors such as MYC and E2F1 to facilitate acetylation of histones, especially H3 at lysine 9 (H3K9). Burkitt lymphoma is an aggressive subtype of Non-Hodgkin lymphoma driven by the overexpression of MYC. Comparison of GCN5 expression in normal human B cells versus human Burkitt Lymphoma cell lines indicates overexpression of GCN5 in lymphoma. Treatment of Burkitt lymphoma cell lines with a specific inhibitor indicates that decreased GCN5 HAT activity reduces viability and proliferation of these cells. Inhibition of GCN5 HAT activity also induces apoptosis in lymphoma cells. Expression of MYC target genes as well as genes associated with B cell receptor signaling are significantly downregulated upon inhibition of GCN5 enzymatic activity. This downregulation leads to diminished PI3K signaling, a critical pathway in lymphomagenesis. Our data indicate that inhibition of GCN5 HAT activity reduces the tumorigenic properties of human Burkitt lymphoma cells by attenuating BCR signaling and that GCN5 may be a viable target for lymphoma drug therapy.

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“…Several papers also have reported that BET inhibitors synergize with cell cycle checkpoint modulators, such as CDK inhibitors or ATR inhibitors . Zhang et al .…”

Section: Discussionmentioning

confidence: 99%

Bromodomain and extraterminal domain inhibition synergizes with WEE1‐inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer

Takashima

Kikuchi

et al. 2019

Intl Journal of Cancer

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Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of BET‐inhibiting drugs on the expression of oncogenes such as c‐Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2‐M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry. Thus, we hypothesized that BET inhibition would increase AZD1775‐induced cytotoxicity by impairing DNA damage repair. Here, we demonstrate that combined inhibition of BET and WEE1 synergistically suppresses NSCLC growth both in vitro and in vivo. Two BET inhibitors, JQ1 and AZD5153, increased and prolonged AZD1775‐induced DNA double‐strand breaks (DSBs) and concomitantly repressed genes related to nonhomologous end joining (NHEJ), including XRCC4 and SHLD1. Furthermore, pharmaceutical inhibition of BET or knockdown of the BET protein BRD4 markedly diminished NHEJ activity, and the BET‐inhibitor treatment also repressed myelin transcription factor 1 (MYT1) expression and promoted mitotic entry with subsequent mitotic catastrophe when combined with WEE1 inhibition. Our findings reveal that BET proteins, predominantly BRD4, play an essential role in DSB repair through the NHEJ pathway, and further suggest that combined inhibition of BET and WEE1 could serve as a novel therapeutic strategy for NSCLC.

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Drug-based perturbation screen uncovers synergistic drug combinations in Burkitt lymphoma

Cited by 26 publications

References 62 publications

High-throughput screening reveals higher synergistic effect of MEK inhibitor combinations in colon cancer spheroids

High-throughput screening reveals higher synergistic effect of MEK inhibitor combinations in colon cancer spheroids

GCN5 HAT inhibition reduces human Burkitt lymphoma cell survival through reduction of MYC target gene expression and impeding BCR signaling pathways

Bromodomain and extraterminal domain inhibition synergizes with WEE1‐inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer

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