Cancer cell · 2021
PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Gozgit Joseph M, Vasbinder Melissa M, Abo Ryan P, Kunii Kaiko, Kuplast-Barr Kristy G, Gui Bin, Lu Alvin Z, Molina Jennifer R, Minissale Elena, Swinger Kerren K, Wigle Tim J, Blackwell Danielle J, Majer Christina R, Ren Yue, Niepel Mario, Varsamis Zacharenia A, Nayak Sunaina P, Bamberg Ellen, Mo Jan-Rung, Church W David, Mady Ahmed S A, Song Jeff, Utley Luke, Rao Patricia E, Mitchison Timothy J, Kuntz Kevin W, Richon Victoria M, Keilhack Heike
Аннотация
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.