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Assessment of Ovarian Cancer Spheroid Attachment and Invasion of Mesothelial Cells in Real Time
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MYC and HSF1 Cooperate to Drive PLK1 inhibitor Sensitivity in High Grade Serous Ovarian Cancer

Imade Williams, Haddie DeHart, Matthew O'Malley

    Biorxiv : the Preprint Server for Biology
    |June 25, 2024
    PubMed

    Insights

    Gene amplification of HSF1 and MYC drives ovarian cancer growth. Targeting PLK1 with volasertib shows promise in HSF1-MYC co-amplified tumors, suggesting a precision medicine approach for this deadly cancer.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Genetics

    Background:

    • Ovarian cancer is a lethal malignancy with high recurrence rates, often developing resistance to platinum-based therapies.
    • Current treatments for ovarian cancer have reached a therapeutic plateau, necessitating novel treatment strategies.
    • A specific gene amplification involving Heat Shock Factor 1 (HSF1) and MYC on chromosome 8q is identified in a subset of human tumors, notably enriched in ovarian cancer patients.

    Purpose of the Study:

    • To investigate the functional cooperation between HSF1 and MYC in ovarian cancer.
    • To identify potential therapeutic targets exploiting the dependency of HSF1-MYC co-amplified ovarian cancer cells.
    • To evaluate the efficacy of targeting PLK1 in ovarian cancer with HSF1-MYC co-amplification.

    Main Methods:

    • Analysis of HSF1 and MYC transcriptional activity correlation in human tumors and cell lines.
    • Chromatin assay for Transposase-Accessible Chromatin using sequencing (CUT&RUN) to map HSF1 and MYC binding sites.
    • Detection of protein-protein interactions between HSF1 and MYC.
    • Assessment of cell growth dependency on HSF1 and MYC.
    • Correlation analysis of PLK1 with HSF1 and MYC in patient specimens.
    • In vitro efficacy testing of PLK1 inhibitor volasertib (BI-6727) in ovarian cancer cells with varying HSF1 and MYC copy numbers.

    Main Results:

    • HSF1 and MYC transcriptional activity is correlated in ovarian cancer, and they exhibit overlapping genomic binding sites and direct protein-protein interaction.
    • Ovarian cancer cells with HSF1-MYC co-amplification are dependent on both transcription factors for growth.
    • PLK1 (Polo Like Kinase 1) expression correlates with HSF1 and MYC levels in tumors.
    • The PLK1 inhibitor volasertib demonstrated significantly enhanced potency (over 200-fold) against HSF1-MYC co-amplified ovarian cancer cells compared to wild-type cells.

    Conclusions:

    • HSF1 and MYC cooperate molecularly and functionally in ovarian cancer, driving tumor growth.
    • PLK1 inhibition, specifically targeting volasertib, shows potential as a therapeutic strategy for ovarian cancer patients with HSF1-MYC co-amplification.
    • HSF1-MYC co-amplification can serve as a predictive biomarker for response to PLK1 inhibitors in a precision medicine context.

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