Related Experiment Video
Updated: Mar 8, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Replication Study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc
Fraser Aird1, Irawati Kandela1, Christine Mantis1
1Developmental Therapeutics Core, Northwestern University, Evanston, United States.
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 7C-D; 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.
Insights
This study replicated experiments on BET bromodomain inhibition for multiple myeloma (MM). (+)-JQ1 downregulated MYC transcription and improved survival in MM models, though tumor burden reduction was not statistically significant.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- BET bromodomain inhibition is a potential therapeutic strategy for cancer.
- The drug (+)-JQ1 targets BET bromodomains and affects MYC transcription.
- Reproducibility Project: Cancer Biology aims to validate key findings in cancer research.
Purpose of the Study:
- To replicate experiments investigating the efficacy of BET bromodomain inhibition in multiple myeloma.
- To validate the effect of (+)-JQ1 on MYC transcription and tumor growth in a preclinical model.
- To assess the specificity of the therapeutic effect using the inactive enantiomer (-)-JQ1.
Main Methods:
- Treatment of human multiple myeloma cells with (+)-JQ1.
- Evaluation of (+)-JQ1 efficacy in an orthotopic xenograft mouse model of multiple myeloma.
- Assessment of MYC transcription levels, overall survival, and tumor burden (bioluminescence).
- Comparison with vehicle control and the inactive enantiomer (-)-JQ1.
Main Results:
- (+)-JQ1 selectively downregulated MYC transcription in multiple myeloma cells, consistent with prior studies.
- Mice treated with (+)-JQ1 showed increased overall survival compared to controls.
- Tumor burden reduction was observed in (+)-JQ1 treated mice, but did not reach statistical significance.
- The inactive enantiomer (-)-JQ1 had minimal impact on MYC transcription and did not significantly affect tumor burden or survival.
Conclusions:
- The study largely reproduced the findings of Delmore et al. (2011) regarding BET bromodomain inhibition in multiple myeloma.
- (+)-JQ1 demonstrates therapeutic potential by downregulating MYC and improving survival.
- Further investigation may be warranted, considering the limitations in statistical significance for tumor burden in this replication study.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:23Abnormal Proliferation
02:38Mitogens and the Cell Cycle
01:06Induced Pluripotent Stem Cells
Somatic...
02:34Inhibition of Cdk Activity
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...