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  • Sir Peter MacCallum Department of Oncology
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    Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress

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    Author
    Nyquist, MD; Corella, A; Coleman, I; De Sarkar, N; Kaipainen, A; Ha, G; Gulati, R; Ang, L; Chatterjee, P; Lucas, J; ...
    Date
    2020-05-26
    Source Title
    Cell Reports
    Publisher
    CELL PRESS
    University of Melbourne Author/s
    Risbridger, Gail
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Nyquist, M. D., Corella, A., Coleman, I., De Sarkar, N., Kaipainen, A., Ha, G., Gulati, R., Ang, L., Chatterjee, P., Lucas, J., Pritchard, C., Risbridger, G., Isaacs, J., Montgomery, B., Morrissey, C., Corey, E. & Nelson, P. S. (2020). Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress. CELL REPORTS, 31 (8), https://doi.org/10.1016/j.celrep.2020.107669.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/252424
    DOI
    10.1016/j.celrep.2020.107669
    Abstract
    Prostate cancers (PCs) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes. TP53 and RB1 also influence cell plasticity and are frequently lost in PCs with neuroendocrine (NE) differentiation. Therapeutic strategies that address these aggressive variant PCs are urgently needed. Using deep genomic profiling of 410 metastatic biopsies, we determine the relationships between combined TP53 and RB1 loss and PC phenotypes. Notably, 40% of TP53/RB1-deficient tumors are classified as AR-active adenocarcinomas, indicating that NE differentiation is not an obligate consequence of TP53/RB1 inactivation. A gene expression signature reflecting TP53/RB1 loss is associated with diminished responses to AR antagonists and reduced survival. These tumors exhibit high proliferation rates and evidence of elevated DNA repair processes. While tumor cells lacking TP53/RB1 are highly resistant to all single-agent therapeutics tested, the combination of PARP and ATR inhibition is found to produce significant responses, reflecting a clinically exploitable vulnerability resulting from replication stress.

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