Abstract 3077: Pharmacological inhibition of NUAK1 and NUAK2 synergizes with chemotherapy in pancreatic cancer models by abrogating drug resistance and suppressing fibrosis

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and treatment-resistance cancers with a 5-year survival rates of around 10%. Since most PDAC cases are diagnosed at an advanced stage, current treatment options are essentially limited to chemotherapy, which is unfortunately barely effective. Therefore, the development of new, innovative therapies is desperately needed. PDAC is characterized by its desmoplastic nature and exceptionally high recurrence rates, both of which are also known to be furthered by chemotherapy. It is hypothesized that therapy-induced cell death exacerbates fibrosis and paradoxically facilitates resistance development. Therefore, concurrent inhibition of these pathways alongside cytotoxic therapy may enhance treatment outcomes in PDAC patients. NUAK family kinase1 and 2 are members of AMP-related kinase family, known to be implicated in cancer progression, cell adhesion, cell proliferation and metastasis. Elevated NUAK1/2 expression correlates with poor prognosis and patient survival rate in many cancer types including pancreatic cancer. Recently, it was also shown that NUAK1 inhibition by genetic knockdown or a chemical inhibitor reduced organ fibrosis via Hippo pathway modulation in mouse models. In this study, we demonstrate anti-chemoresistance and anti-fibrotic activities of P4899, a potent and selective NUAK1/2 dual inhibitor, in pancreatic cancer. Treatment of pancreatic cell lines with chemotherapeutic agents such as gemcitabine and cisplatin initially causes massive cell death, but the surviving cells undergo hyperploidy that eventually leads to repopulation of para-diploid cells, mimicking chemoresistance and tumor recurrence. In the presence of P4899, however, the number of the transient hyperploid cells as well as ensuing repopulation was dramatically reduced. Furthermore, administration of the orally bioavailable NUAK1/2 inhibitor in combination with gemcitabine in a mouse orthotopic PDAC model resulted in significant inhibition of tumor growth as well as reduction of collagen deposition and expression levels of fibrotic genes in tumor tissue. These data suggest that NUAK1/2 inhibition can effectively ameliorate desmoplasia and impede the development of chemo-resistance in pancreatic tumors, which warrants further investigation in the clinical setting. Citation Format: Minji Seo, Jihye Yoon, Song-Eun Park, Jong-Won Lim, Sungho Park, Yuntae Kim, Taeyoung Yoon. Pharmacological inhibition of NUAK1 and NUAK2 synergizes with chemotherapy in pancreatic cancer models by abrogating drug resistance and suppressing fibrosis [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 3077.