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dc.contributor.authorNyquist, MD
dc.contributor.authorCorella, A
dc.contributor.authorColeman, I
dc.contributor.authorDe Sarkar, N
dc.contributor.authorKaipainen, A
dc.contributor.authorHa, G
dc.contributor.authorGulati, R
dc.contributor.authorAng, L
dc.contributor.authorChatterjee, P
dc.contributor.authorLucas, J
dc.contributor.authorPritchard, C
dc.contributor.authorRisbridger, G
dc.contributor.authorIsaacs, J
dc.contributor.authorMontgomery, B
dc.contributor.authorMorrissey, C
dc.contributor.authorCorey, E
dc.contributor.authorNelson, PS
dc.date.accessioned2020-11-27T00:19:27Z
dc.date.available2020-11-27T00:19:27Z
dc.date.issued2020-05-26
dc.identifierpii: S2211-1247(20)30622-7
dc.identifier.citationNyquist, 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.
dc.identifier.issn2211-1247
dc.identifier.urihttp://hdl.handle.net/11343/252424
dc.description.abstractProstate 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.
dc.languageEnglish
dc.publisherCELL PRESS
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.titleCombined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress
dc.typeJournal Article
dc.identifier.doi10.1016/j.celrep.2020.107669
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.source.titleCell Reports
melbourne.source.volume31
melbourne.source.issue8
dc.rights.licensecc-by-nc-nd
melbourne.elementsid1451472
melbourne.contributor.authorRisbridger, Gail
dc.identifier.eissn2211-1247
melbourne.accessrightsOpen Access


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