RBN-2397, a PARP7 Inhibitor, Synergizes with Paclitaxel to Inhibit Proliferation and Migration of Ovarian Cancer Cells.

Mono ADP-ribosylation, a post translational modification of proteins, is emerging as an important regulator of the biology of cancer cells. We showed previously that PARP7 (TiPARP), a mono (ADP-ribosyl) transferase (MART), was found to target α-tubulin proteins in ovarian cancer cells, enhancing their growth and migration. Recent development of RBN-2397, a potent inhibitor that selectively acts on PARP7, has provided a new tool for exploring the role of PARP7 catalytic activity in biological processes. In this study, we investigated the role of PARP7 catalytic activity in the regulation of ovarian cancer cell biology via MARylation of α-tubulin. When ovarian cancer cells were treated with RBN-2397, we observed a decrease in their growth and migration and, interestingly, the effect was intensified upon adding the microtubule stabilizing chemotherapeutic agent, paclitaxel. Mutating the site of PARP7-mediated α-tubulin MARylation similarly resulted in α-tubulin stabilization and decreased cell migration in the presence of paclitaxel. In summary, we demonstrated that PARP7 inhibition decreased α-tubulin MARylation resulting in its stabilization, and ultimately leading to decreased ovarian cancer cell proliferation and migration. Finally, we observed that combining RBN-2397 and paclitaxel resulted in a more robust inhibition of aggressive ovarian cancer cell phenotypes. Collectively, this study highlighted the potential of targeting PARP7 in combination with established chemotherapeutic agents to enhance treatment efficacy for ovarian cancer.