Abstract 6876: A novel PCNA inhibitor AOH1996 demonstrates pre-clinical efficacy in pancreatic ductal adenocarcinoma models

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis. It is the 9th most common cancer, and the 3rd leading cause of mortality in cancer patients in the United States. PDAC poses a significant clinical challenge partly due to advanced disease stage at diagnosis, poor response to chemotherapeutics, and common recurrence. Proliferating cell nuclear antigen (PCNA) is a ring-shaped clamp protein that encircles DNA and regulates replication and repair. Cancer cells depend on PCNA-mediated DNA repair, and transcription-replication conflict resolution to tolerate DNA damage, thus promoting proliferation. AOH1996 is a novel selective PCNA inhibitor in phase I clinical trials for solid tumors. AOH1996 disrupts the association between PCNA and its numerous binding proteins, thereby inhibiting PCNA functions such as DNA replication, and damage repair. In this study, we investigated the use of AOH1996 in preclinical models of pancreatic ducal adenocarcinoma (PDAC). Methods: We determined cell viability and growth inhibition by MTT, colony formation and spheroid assays. Drug combinations of AOH1996 with KRAS inhibitors and chemotherapy were analyzed using synergy finder. Results: We demonstrated that AOH1996 inhibits the growth of a panel of PDAC tumor cells in a dose-dependent manner, in 2D and 3D culture models and clonogenic assays. Cell cycle analysis revealed that AOH1996 causes S-phase arrest in PDAC cells, indicating that S-phase arrest prevents tumor cell growth by targeting DNA replication and repair processes supporting further investigation into AOH1996 to target PDAC. Transcriptomic analysis using RNA sequencing is ongoing to examine the underlying molecular mechanisms of AOH1996 activity. KRAS is the most common oncogenic driver in PDAC and is one of the main synthetic lethal targets with PCNA. Therefore, we examined the combination of emerging KRAS inhibitors with AOH1996 on PDAC models. We found that KRAS G12D inhibitor (MRTX1133) in combination with AOH1996 enhanced cytotoxicity in several PDAC cell lines at lower MRTX1133 concentrations, potentially reducing toxic side effects. We also observed enhanced efficacy of the chemotherapeutic agent oxaliplatin, which is a platinum compound in the FOLFIRINOX regimen, in combination with AOH1996. This indicates that AOH1996 has great potential at improving responses to current and emerging treatments for PDAC patients. Conclusion: Collectively, our results show that AOH1996 is a promising agent for PDAC treatment which potentiates chemotherapy, and targeted KRAS G12D inhibitors. In vivo xenograft studies combining AOH1996 and KRAS inhibitors are ongoing. Citation Format: Sahar F. Bannoura, Husain Y. Khan, Md Hafiz Uddin, Amro Aboukameel, Bin Bao, Khalil Choucair, Yang Shi, Rund Nimri, Eliza W. Beal, Hugo Jimenez, Mohammad Najeeb Al Hallak, Muhammad Wasif Saif, Philip A. Philip, Bassel El-Rayes, Ramzi M. Mohammad, Boris C. Pasche, Long Gu, Linda Malkas, Asfar S. Azmi. A novel PCNA inhibitor AOH1996 demonstrates pre-clinical efficacy in pancreatic ductal adenocarcinoma models [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 6876.