Systematic identification of genomic markers of drug sensitivity in cancer cells

The Reproducibility Project: Cancer Biology seeks to address growing concerns about the reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (<xref ref-type="bibr" rid="bib7">Errington et al., 2014</xref>). This Registered Report describes the proposed replication plan of key experiments from “Systematic identification of genomic markers of drug sensitivity in cancer cells” by Garnett and colleagues, published in Nature in 2012 (<xref ref-type="bibr" rid="bib9">Garnett et al., 2012</xref>). The experiments to be replicated are those reported in Figures 4C, 4E, 4F, and Supplemental Figures 16 and 20. Garnett and colleagues performed a high throughput screen assessing the effect of 130 drugs on 639 cancer-derived cell lines in order to identify novel interactions for possible therapeutic approaches. They then tested this approach by exploring in more detail a novel interaction they identified in which Ewing’s sarcoma cell lines showed an increased sensitivity to PARP inhibitors (Figure 4C). Mesenchymal progenitor cells (MPCs) transformed with the signature EWS-FLI1 translocation, the hallmark of Ewing’s sarcoma family tumors, exhibited increased sensitivity to the PARP inhibitor olaparib as compared to MPCs transformed with a different translocation (Figure 4E). Knockdown mediated by siRNA of EWS-FLI1 abrogated this sensitivity to olaparib (Figure 4F). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.

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Author response: Registered report: Systematic identification of genomic markers of drug sensitivity in cancer cells

10.7554/elife.13620.004 ◽

2016 ◽

Author(s):

John P Vanden Heuvel ◽

Jessica Bullenkamp ◽

Keyword(s):

Cancer Cells ◽

Drug Sensitivity ◽

Author Response ◽

Genomic Markers ◽

Systematic Identification

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Replication Study: Systematic identification of genomic markers of drug sensitivity in cancer cells

eLife ◽

10.7554/elife.29747 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 6

Author(s):

John P Vanden Heuvel ◽

Ewa Maddox ◽

Samar W Maalouf ◽

Elizabeth Iorns ◽

Rachel Tsui ◽

...

Keyword(s):

Cell Lines ◽

Drug Sensitivity ◽

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Mesenchymal Cells ◽

Original Study ◽

Sarcoma Cell ◽

Sarcoma Cell Line ◽

Genomic Markers ◽

Systematic Identification

In 2016, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Vanden Heuvel et al., 2016), that described how we intended to replicate selected experiments from the paper ‘Systematic identification of genomic markers of drug sensitivity in cancer cells’ (Garnett et al., 2012). Here we report the results. We found Ewing’s sarcoma cell lines, overall, were more sensitive to the PARP inhibitor olaparib than osteosarcoma cell lines; however, while the effect was in the same direction as the original study (Figure 4C; Garnett et al., 2012), it was not statistically significant. Further, mouse mesenchymal cells transformed with either the EWS-FLI1 or FUS-CHOP rearrangement displayed similar sensitivities to olaparib, whereas the Ewing’s sarcoma cell line SK-N-MC had increased olaparib sensitivity. In the original study, mouse mesenchymal cells transformed with the EWS-FLI1 rearrangement and SK-N-MC cells were found to have similar sensitivities to olaparib, whereas mesenchymal cells transformed with the FUS-CHOP rearrangement displayed a reduced sensitivity to olaparib (Figure 4E; Garnett et al., 2012). We also studied another Ewing’s sarcoma cell line, A673: A673 cells depleted of EWS-FLI1 or a negative control both displayed similar sensitivities to olaparib, whereas the original study reported a decreased sensitivity to olaparib when EWS-FLI1 was depleted (Figure 4F; Garnett et al., 2012). Differences between the original study and this replication attempt, such as the use of different sarcoma cell lines and level of knockdown efficiency, are factors that might have influenced the outcomes. Finally, where possible, we report meta-analyses for each result.

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Group-sparse Modeling Drug-kinase Networks for Predicting Combinatorial Drug Sensitivity in Cancer Cells

Current Bioinformatics ◽

10.2174/1574893613666180118104250 ◽

2018 ◽

Vol 13 (5) ◽

pp. 437-443 ◽

Cited By ~ 8

Author(s):

Hui Liu ◽

Libo Luo ◽

Zhanzhan Cheng ◽

Jianjiang Sun ◽

Jihong Guan ◽

...

Keyword(s):

Cancer Cells ◽

Drug Sensitivity ◽

Sparse Modeling

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HER2 decreases drug sensitivity of ovarian cancer cells via inducing stem cell-like property in an NFκB-dependent way

Bioscience Reports ◽

10.1042/bsr20180829 ◽

2019 ◽

Vol 39 (3) ◽

Cited By ~ 1

Author(s):

Wenxiang Wang ◽

Yuxia Gao ◽

Jing Hai ◽

Jing Yang ◽

Shufeng Duan

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Drug Sensitivity ◽

Ovarian Cancer Cells ◽

Her2 Overexpression ◽

Her2 Positive ◽

Ovarian Cancer Stem Cells

Abstract Increasing evidence shows that cancer stem cells are responsible for drug resistance and relapse of tumors. In breast cancer, human epidermal growth factor receptor 2 (HER2) induces Herceptin resistance by inducing cancer stem cells. In the present study, we explored the effect of HER2 on cancer stem cells induction and drug sensitivity of ovarian cancer cell lines. First, we found that HER2 overexpression (HER2 OE) induced, while HER2 knockdown (HER2 KD) decreased CD44+/CD24− population. Consistently, HER2 expression was closely correlated with the sphere formation efficiency (SFE) of ovarian cancer cells. Second, we found that NFκB inhibition by specific inhibitor JSH23 or siRNA targetting subunit p65 dramatically impaired the induction of ovarian cancer stem cells by HER2, indicating that NFκB mediated HER2-induced ovarian cancer stem cells. Third, we found that HER2 KD significantly attenuated the tumorigenicity of ovarian cancer cells. Further, we found that HER2 inhibition increased drastically the sensitivity of ovarian cancer cells to doxorubicin (DOX) or paclitaxel (PTX). Finally, we examined the correlation between HER2 status and stem cell-related genes expression in human ovarian tumor tissues, and found that expressions of OCT4, COX2, and Nanog were higher in HER2 positive tumors than in HER2 negative tumors. Consistently, the 5-year tumor-free survival rate of HER2 positive patients was dramatically lower than HER2 negative patients. Taken together, our data indicate that HER2 decreases drug sensitivity of ovarian cancer cells via inducing stem cell-like property.

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