Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress. Cell Rep 2020 May 26;31(8):107669
Date
05/28/2020Pubmed ID
32460015Pubmed Central ID
PMC7453577DOI
10.1016/j.celrep.2020.107669Scopus ID
2-s2.0-85085319793 (requires institutional sign-in at Scopus site) 132 CitationsAbstract
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.
Author List
Nyquist MD, 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 PSAuthor
Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Biomarkers, TumorCell Proliferation
Humans
Male
Prostatic Neoplasms
Retinoblastoma Binding Proteins
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases
