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

• Published in: Cancer research communications 2023-04, Vol.3 (4), p.592-606
• Main Authors: Yang, Chunsong, Wierbiłowicz, Krzysztof, Dworak, Natalia M, Bae, Song Yi, Tengse, Sachi B, Abianeh, Nicki, Drake, Justin M, Abbas, Tarek, Ratan, Aakrosh, Wotton, David, Paschal, Bryce M
• Format: Article
• Language: English
• Subjects: ADP Ribose Transferases - genetics; Androgens; Biochemistry; Drug Mechanisms; Drug Targets; Gene Regulation; Genitourinary Cancers; Humans; Male; Prostate - metabolism; Prostatic Neoplasms - drug therapy; Receptors, Androgen - genetics; Small Molecule Agents
• ISSN: 2767-9764; 2767-9764
• DOI: 10.1158/2767-9764.CRC-23-0086

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 (AR)-positive and AR-negative prostate cancer cells. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the AR. RBN2397 inhibits the growth of prostate cancer cells in culture when cells are treated with ligands that activate the AR, or the aryl hydrocarbon receptor, and induce PARP7 expression. We show that the growth-inhibitory effects of RBN2397 are distinct from its enhancement of IFN signaling recently shown to promote tumor immunogenicity. RBN2397 treatment also induces trapping of PARP7 in a detergent-resistant fraction within the nucleus, which is reminiscent of how inhibitors such as talazoparib affect PARP1 compartmentalization. Because PARP7 is expressed in AR-negative metastatic tumors and RBN2397 can affect cancer cells through multiple mechanisms, PARP7 may be an actionable target in advanced prostate cancer. RBN2397 is a potent and selective inhibitor of PARP7 that reduces the growth of prostate cancer cells, including a model for treatment-emergent neuroendocrine prostate cancer. RBN2397 induces PARP7 trapping on chromatin, suggesting its mechanism of action might be similar to clinically used PARP1 inhibitors.