Replication study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc

Fraser Aird, Irawati Kandela, Christine Mantis, Elizabeth Iorns, Alexandria Denis, Stephen R. Williams, Nicole Perfito, Timothy M. Errington*

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper “BET bromodomain inhibition as a therapeutic strategy to target c-Myc” (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated MYC transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al., 2011). Efficacy of (+)-JQ1 was evaluated in an orthotopically xenografted model of MM. Overall survival was increased in (+)-JQ1 treated mice compared to vehicle control, similar to the original study (Figure 7E; Delmore et al., 2011). Tumor burden, as determined by bioluminescence, was decreased in (+)-JQ1 treated mice compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 7CD; Delmore et al., 2011), it was not statistically significant. The opportunity to detect a statistically significant difference was limited though, due to the higher rate of early death in the control group, and increased overall survival in (+)-JQ1 treated mice before the pre-specified tumor burden analysis endpoint. Additionally, we evaluated the (-)-JQ1 enantiomer that is structurally incapable of inhibiting BET bromodomains, which resulted in a minimal impact on MYC transcription, but did not result in a statistically significant difference in tumor burden or survival distributions compared to treatment with (+)-JQ1. Finally, we report meta-analyses for each result.

Original languageEnglish (US)
Article numbere21253
JournaleLife
Volume6
DOIs
StatePublished - Jan 19 2017

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Aird, F., Kandela, I., Mantis, C., Iorns, E., Denis, A., Williams, S. R., Perfito, N., & Errington, T. M. (2017). Replication study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc. eLife, 6, [e21253]. https://doi.org/10.7554/eLife.21253