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The novel low molecular weight MYC antagonist MYCMI-6 inhibits proliferation and induces apoptosis in breast cancer cells

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Summary

Background The MYC oncogene is one of the most frequently altered driver genes in cancer. MYC is thus a potential _target for cancer treatment as well as a biomarker for the disease. However, as a _target for treatment, MYC has traditionally been regarded as “undruggable” or difficult to _target. We set out to evaluate the efficacy of a novel MYC inhibitor known as MYCMI-6, which acts by preventing MYC from interacting with its cognate partner MAX. Methods MYCMI-6 response was assessed in a panel of breast cancer cell lines using MTT assays and flow cytometry. MYC gene amplification, mRNA and protein expression was analysed using the TCGA and METABRIC databases. Results MYCMI-6 inhibited cell growth in breast cancer cell lines with IC50 values varying form 0.3 μM to >10 μM. Consistent with its ability to decrease cell growth, MYCMI-6 was found to induce apoptosis in two cell lines in which growth was inhibited but not in two cell lines that were resistant to growth inhibition. Across all breast cancers, MYC was found to be amplified in 15.3% of cases in the TCGA database and 26% in the METABRIC database. Following classification of the breast cancers by their molecular subtypes, MYC was most frequently amplified and exhibited highest expression at both mRNA and protein level in the basal subtype. Conclusions Based on these findings, we conclude that for patients with breast cancer, anti-MYC therapy is likely to be most efficacious in patients with the basal subtype.

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Fig. 1
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Data availability

Bioinformatic data was retrieved from the TCGA and METABRIC datasets, which can be accessed via the TCGA-Data portal (https://portal.gdc.cancer.gov/) and cBioportal (https://www.cbioportal.org/study/summary?id=brca_metabric) respectively.

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Funding

We thank the Cancer Clinical Research Trust and the Irish Research Council (EPSPG/2019/507) for funding this work.

Author information

Author notes

  1. Dalal AlSultan and Emma Kavanagh contributed equally to this work and should be considered as joint first authors.

    Stephen F Madden and Michael J Duffy contributed equally to this work and should be considered as joint last authors.

Authors and Affiliations

  1. Data Science Centre, Royal College of Surgeons in Ireland, Beaux Lane House, Dublin, Ireland

    Dalal AlSultan & Stephen F Madden

  2. National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland

    Dalal AlSultan & Alex J Eustace

  3. UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland

    Emma Kavanagh, Shane O’Grady & Michael J Duffy

  4. Education & Research Centre, St Vincent’s University Hospital, Elm Park, Dublin, Ireland

    Shane O’Grady

  5. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

    Alina Castell & Lars-Gunnar Larsson

  6. Department of Medical Oncology, St Vincent’s University Hospital, Dublin, Ireland

    John Crown

  7. Clinical Research Centre, St Vincent’s University Hospital, Dublin, Ireland

    Michael J Duffy

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  1. Dalal AlSultan
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Contributions

DAS performed the bioinformatics analysis of TCGA and METABRIC databases. EK performed the cell growth and apoptosis experiments. SOG analysed the results of the cell line studies and constructed Figs. 1-3. AJE co-supervised the bioinformatics analysis. AC and LGL discovered and validated the MYCMI-6 inhibitor. JC contributed to the writing of the manuscript with particular input to potential clinical applications of our findings. SFM supervised the bioinformatic analysis and wrote this section of the manuscript. MJD conceived the project and supervised the cell line studies. All authors contributed to the writing of the manuscript.

Corresponding author

Correspondence to Shane O’Grady.

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Conflict of interest

DA, SO’G, EK, AJE, AC, LGL, SM & MJD have no conflicts of interest. JC has received honoraria from Eisai, Amgen, Puma Biothechnology, Seattle Genetics, Boehringer Ingelheim, Pfizer, Vertex and Genomic Health. He has acted in an advisory/consulting role to Eisai, Puma Biotechnology, Boehringer Ingelheim, Pfizer, Vertex, Roche. He also serves on the Speakers’ Bureau for Pfizer, Eisai and Genomic Health and has received Research Funding from Roche, Eisai, Boehringer Ingelheim and Puma Biotechnology. In addition, he has received travel, accommodation and expenses from MSD, Pfizer, Roche, AstraZeneca, Abbvie and Novartis. Finally, he is an employee of OncoMark, has stocks in OncoMark and is named on patent WO2020011770 (A1) - A method of predicting response to treatment in cancer patients.

Ethical approval

This study utilised commercially available cell lines and bioinformatics analysis of previously published, publicly available databases. No human or animal subjects were used in this study.

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For this type of study, formal consent is not required.

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ESM 1

Kaplan-Meier overall survival (OS) curve for the total population of breast cancer patients with high MYC amplification from METABRIC (A) and TCGA (B). P-values, HR and 95% confidence interval (CI) are shown. Kaplan-Meier OS curve plotting the survival probability of breast cancer patients with the basal PAM50 subtype in METABRIC (C) and TCGA (D). P-values, HR and 95% CI are shown. (PDF 383 kb)

ESM 2

Kaplan-Meier OS curves for MYC mRNA levels, dichotomized based on median expression levels for total population of breast cancer patients for METABRIC (A) and TCGA (B). P-values, HR and 95% CI are shown. Kaplan-Meier OS curves for MYC mRNA levels, dichotomized based on median expression levels for breast cancer patients with basal PAM50 subtype in METABRIC (C) and TCGA (D). P-values, HR and 95% CI are shown. (PDF 386 kb)

ESM 3

Kaplan-Meier overall survival curve for MYC protein levels for total population of breast cancer patients (A) and in the PAM50 basal subtype of breast cancer (B). P-values, HR and 95% CI are shown. (PDF 227 kb)

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AlSultan, D., Kavanagh, E., O’Grady, S. et al. The novel low molecular weight MYC antagonist MYCMI-6 inhibits proliferation and induces apoptosis in breast cancer cells. Invest New Drugs 39, 587–594 (2021). https://doi.org/10.1007/s10637-020-01018-w

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