Abstract 5717: Nesuparib, a dual inhibitor of PARP and tankyrase, is efficacious in preclinical gastric cancer models by regulation of HIPPO and Wnt pathway

Gastric cancer is the fifth most common cancer and it still needs to identify novel actionable targets to bring clinical benefits. Here we explored the efficacy of nesuparib, a dual inhibitor for poly-ADP-ribosyl transferase 1/2 (PARP 1/2) and tankyrase 1/2 (TNKS 1/2) in vitro and in vivo models using BRCA wild type gastric cell lines. In addition to PARP 1/2 inhibition, nesuparib selectively inhibits TNKS 1 and 2 enzymatic activities; TNKS is a member of PARP family, and poly-ribosylates target proteins that are involved in Wnt/β-catenin and Hippo signaling pathways. The poly-ribosylated proteins are subsequently ubiquitinated by E3 ligases and undergo proteasomal degradation. The inhibition of TNKS is known to attenuate cancer promoting signaling like Wnt and Hippo signaling. To evaluate the impact of nesuparib on cell growth, half maximal inhibitory concentration (IC50) of nesuparib, Olaparib, and XAV939 in clonogenicity was compared in BRCA wild type gastric cancer cells. Nesuparib is at least 28-fold more potent than Olaparib and 13-fold more potent than XAV939 among cell lines. To examine how nesuparib modulates Wnt/β-catenin and Hippo signaling through TNKS inhibition, we assessed changes in canonical Wnt/β-catenin and Hippo signaling-related molecules at protein levels. Nesuparib stabilized AXIN, reducing nonphospho β-catenin, c-myc, and cyclin D1. In addition, nesuparib stabilized AMOT proteins and increased phospho-YAP reflecting inhibition of the oncogenic YAP pathway. Given the findings that nesuparib treatment regulates Wnt and Hippo signaling in KATO III and NCI-N87 cells (BRCA wild type), we tested its efficacy as a single or with a combination of irinotecan in these cell line xenograft mouse models. Nesuparib showed superior potency than Olaparib alone in both xenograft models. The combination of nesuparib with irinotecan enhanced the anti-tumor activity compared with nesuparib single treatment. In addition, the combination of nesuparib with irinotecan showed stronger tumor growth suppression than the combination of Olaparib with irinotecan.In summary, these results suggest that nesuparib may exert anti-tumor efficacy in specific types of cancers with pro-cancerous signaling of the Wnt or Hippo pathway by the regulation of TNKS. This warrants a proof-of-concept of anti-tumor effect of nesuparib in gastric cancers and its potentials for clinical benefits. Citation Format: Banyoon Cheon, Jung Young Shin, Dae-In PARK, Jun Kim, John Kim, Hyunju Cha. Nesuparib, a dual inhibitor of PARP and tankyrase, is efficacious in preclinical gastric cancer models by regulation of HIPPO and Wnt pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5717.