PROSTATE CANCER: Genomic alterations resulting in combined disruption of TP53 and RB1 is associated with poor survival and treatment resistance, but potential vulnerability to PARP + ATR inhibition in preclinical models.
Genomic alterations resulting in combined disruption of TP53 and RB1 is associated with poor survival and treatment resistance, but potential vulnerability to PARP + ATR inhibition in preclinical models
Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress
• Prostate cancers (PCs) with TP53 and RB1 loss exhibit very poor clinical outcomes
• PCs with TP53/RB1 loss exhibit stem cell-like features and loss of AR activity
• Loss of TP53/RB1 does not uniformly promote neuroendocrine transdifferentiation
• TP53/RB1-null PCs exhibit replication stress and respond to PARP and ATR inhibition
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.