Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells

The ADP-ribosyltransferase PARP7 modulates protein function by conjugating ADP-ribose to the side chains of acceptor amino acids. PARP7 has been shown to affect gene expression in prostate cancer cells and certain other cell types by mechanisms that include transcription factor ADP-ribosylation. Here, we use a recently developed catalytic inhibitor to PARP7, RBN2397, to study the effects of PARP7 inhibition in androgen receptor-positive and androgen receptor-negative prostate cancer cells. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the androgen receptor. RBN2397 inhibits the growth of prostate cancer cells in culture, mainly when cells are treated with ligands that either activate the androgen receptor, or the aryl hydrocarbon receptor, and induce PARP7 expression. We show that the growth inhibitory effects of RBN2397 are distinct from its enhancement of interferon signaling recently shown to promote tumor immunogenicity. RBN2397 treatment also induces biochemical trapping of PARP7 within the nucleus, which is reminiscent of how inhibitors such as Olaparib affect PARP1. Because RBN2397 can affect cancer cells through multiple mechanisms, PARP7 may be an actionable target in prostate cancer.