Abstract 4496: JPI-547, a dual inhibitor of PARP/Tankyrase, shows promising antitumor activity against pancreatic cancers with homologous recombination repair deficiency or Wnt-addiction
Authors: Oh Kyoung-Seok , Nam Ah-Rong , Bang Ju-Hee , Jeong Yoojin , Choo Sea Young , Kim Hyo Jung , Lee Su In , Kim Jae-Min , Yoon Jeesun , Kim Tae-Yong , Cheon Banyoon , Cha Hyunju , Kim John , Oh Do-Youn 
Published: April 2023

Abstract
Background: PARP inhibitors have shown antitumor activities against solid tumors with HRD (homologous recombination deficiency). The definition of HRD and other potential biomarkers besides HRD should be further evaluated for PARP inhibitors. JPI-547 is a novel PARP inhibitor, simultaneously targeting tankyrase1/2, other members of the PARP family, that are involved in the Wnt/β-catenin pathway.
Method: Antiproliferative effect of JPI-547 and a variety of PARP inhibitors (olaparib, veliparib, talazoparib, niraparib, and rucaparib) were determined by MTT assay or clonogenic assay in 9 human pancreatic ductal adenocarcinoma (PDAC) cell lines (Capan-1, HPAF-II, Capan-2, AsPC-1, SNU-410, SNU-213, SNU-324, MIA-PaCa2, and PANC-1). Transcriptome data and gene dependency score of the cell lines were obtained from the CCLE database and DepMap respectively. DNA damage was monitored by immunofluorescent imaging of γ-H2AX and DR-GFP assay determined the homologous recombination repair (HRR) efficiency. A xenograft tumor model was established to substantiate the in vivo antitumor effect of JPI-547.
Results: JPI-547 more potently blocks Poly(ADP-ribosyl)ation than olaparib, and induces a strong antiproliferative effect on Capan-1, a cell line with BRCA2 del. JPI-547 leads to cell cycle arrest and induces enhanced apoptotic cell death than olaparib. JPI-547 inhibits tumor growth of Capan-1 in vivo, suggesting the potent antitumor activity of JPI-547 against PDAC with HRD. Cell lines harboring RNF43 LOF mutations (HPAF-II, AsPC-1, and Capan-2), intrinsically addicted to Wnt/β-catenin pathway, are more sensitive to JPI-547 than cells with RNF43 wild types. Interestingly, RNF43 mutations could not distinguish the sensitivity of other PARP inhibitors except JPI-547. CTNNB1 gene dependency score and β-catenin levels positively correlate with cellular sensitivity to JPI-547. JPI-547-induced DNA damage was alleviated in HR-proficient PDAC cells. DR-GFP assays confirm that JPI-547 does not directly alter the HRR efficiency of Wnt-addicted PDAC cells. Collectively, these data indicate that the vulnerabilities of Wnt-addicted PDAC cells to JPI-547 were irrelevant to HRD mimicking. Rather, JPI-547 stabilizes AXIN-2 in Wnt-addicted PDAC cells and downregulates the active form of β-catenin level in the nucleus, thereby disrupting the transcription of its target genes. Knockdown of β-catenin neutralized the antiproliferative effect of JPI-547, suggesting that inhibition of the β-catenin pathway is an important mode of action by JPI-547 in Wnt-addicted PDAC cells.
Conclusion: JPI-547 shows promising, preclinical antitumor effects against PDAC cells with HRD or Wnt-addiction, providing a rationale for further biomarker-driven clinical development of JPI-547 for the treatment of patients with PDAC.
Citation Format: Kyoung-Seok Oh, Ah-Rong Nam, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Su In Lee, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Banyoon Cheon, Hyunju Cha, John Kim, Do-Youn Oh. JPI-547, a dual inhibitor of PARP/Tankyrase, shows promising antitumor activity against pancreatic cancers with homologous recombination repair deficiency or Wnt-addiction. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4496.