PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity
Joseph M Gozgit, Melissa M Vasbinder, Ryan P Abo, Kaiko Kunii, Kristy G Kuplast-Barr, Bin Gui, Alvin Z Lu, Jennifer R Molina, Elena Minissale, Kerren K Swinger, Tim J Wigle, Danielle J Blackwell, Christina R Majer, Yue Ren, Mario Niepel, Zacharenia A Varsamis, Sunaina P Nayak, Ellen Bamberg, Jan-Rung Mo, W David Church, Ahmed S A Mady, Jeff Song, Luke Utley, Patricia E Rao, Timothy J Mitchison, Kevin W Kuntz, Victoria M Richon, Heike Keilhack, Joseph M Gozgit, Melissa M Vasbinder, Ryan P Abo, Kaiko Kunii, Kristy G Kuplast-Barr, Bin Gui, Alvin Z Lu, Jennifer R Molina, Elena Minissale, Kerren K Swinger, Tim J Wigle, Danielle J Blackwell, Christina R Majer, Yue Ren, Mario Niepel, Zacharenia A Varsamis, Sunaina P Nayak, Ellen Bamberg, Jan-Rung Mo, W David Church, Ahmed S A Mady, Jeff Song, Luke Utley, Patricia E Rao, Timothy J Mitchison, Kevin W Kuntz, Victoria M Richon, Heike Keilhack
Abstract
PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. Here, we identify PARP7 as a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 restores type I interferon (IFN) signaling responses to nucleic acids in tumor models. Restored signaling can directly inhibit cell proliferation and activate the immune system, both of which contribute to tumor regression. Oral dosing of the PARP7 small-molecule inhibitor, RBN-2397, results in complete tumor regression in a lung cancer xenograft and induces tumor-specific adaptive immune memory in an immunocompetent mouse cancer model, dependent on inducing type I IFN signaling in tumor cells. PARP7 is a therapeutic target whose inhibition induces both cancer cell-autonomous and immune stimulatory effects via enhanced IFN signaling. These data support the targeting of a monoPARP in cancer and introduce a potent and selective PARP7 inhibitor to enter clinical development.
Keywords: DNA sensing; PARP7; RBN-2397; cancer drug discovery; innate immunity; nucleic acid sensing; small-molecule inhibitor; type I interferon.
Conflict of interest statement
Declaration of interests J.M.G., M.M.V., R.P.A., K.K., K.G.K.-B., B.G., A.Z.L., J.R. Molina, E.M., K.K.S., T.J.W., D.J.B., C.R.M., Y.R., M.N., Z.A.V., S.P.N., E.B., J.-R. Mo, W.D.C., A.S.A.M., J.S., L.U., K.W.K., V.M.R., and H.K. are all employees and shareholders of Ribon Therapeutics at the time of data collection. P.E.R. served as a consultant to Ribon Therapeutics, and T.J.M. is a founder and shareholder in Ribon Therapeutics. M.M.V., K.K.S., and K.W.K. are inventors on US Patent Nos. 10550105, 10870641, and 11014913, which are related to RBN-2397 and assigned to Ribon Therapeutics.
Copyright © 2021 Elsevier Inc. All rights reserved.
Source: PubMed