1. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity.
- Author
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Gozgit JM, Vasbinder MM, Abo RP, Kunii K, Kuplast-Barr KG, Gui B, Lu AZ, Molina JR, Minissale E, Swinger KK, Wigle TJ, Blackwell DJ, Majer CR, Ren Y, Niepel M, Varsamis ZA, Nayak SP, Bamberg E, Mo JR, Church WD, Mady ASA, Song J, Utley L, Rao PE, Mitchison TJ, Kuntz KW, Richon VM, and Keilhack H
- Subjects
- Adaptive Immunity drug effects, Animals, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, HEK293 Cells, HeLa Cells, Humans, Mice, Neoplasms genetics, Neoplasms metabolism, Signal Transduction drug effects, Small Molecule Libraries pharmacology, Tumor Escape drug effects, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm drug effects, Interferon Type I metabolism, Neoplasms drug therapy, Nucleoside Transport Proteins genetics, Nucleoside Transport Proteins metabolism, Small Molecule Libraries administration & dosage
- 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., Competing Interests: 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.)
- Published
- 2021
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