Targeting the DDX3/PAF1 Axis Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma

Palanisamy Nallasamy; Parthasarathy Seshacharyulu; Sanchita Rauth; Ashu Shah; Saravanakumar Marimuthu; Venkatesh Varadharaj; Madhulatha Bommideni; Kavita Mallya; Zahraa Wajih Alsafwani; Subodh M Lele; Venu Raman; Surinder K Batra; Moorthy P Ponnusamy

doi:10.1016/j.canlet.2026.218276

Targeting the DDX3/PAF1 Axis Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma

Cancer Lett. 2026 Jan 23:218276. doi: 10.1016/j.canlet.2026.218276. Online ahead of print.

Affiliations

¹ Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
² Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
³ Departments of Radiology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: sbatra@unmc.edu.
⁵ Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: mpalanim@unmc.edu.

PMID: 41581643
DOI: 10.1016/j.canlet.2026.218276

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that has a poor survival rate of ∼13% with limited options for effective therapies. DDX3 is a member of the DEAD-box RNA helicase enzyme family. It acts as an adapter protein that interacts with several transcription factors, enhancing their binding ability to the promoters of genes involved in cancer progression. Previously, we demonstrated that PAF1, a component of the RNA polymerase II-associated factor 1 complex, interacts with DDX3 to promote PDAC stemness. Here, we investigated the therapeutic efficacy of RK-33, a small molecule inhibitor targeting DDX3, in combination with gemcitabine (GEM) and 5-fluorouracil (5FU), which enhances the therapeutic efficacy in KRAS-driven PDAC. DDX3 and PAF1 exhibit progressively increased expression in various stages and correlate well with poor survival of PDAC. Targeting DDX3/PAF1 significantly mitigated clonogenic, EMT, and stemness phenotypes in PDAC cells. It also reduced tumor growth, proliferation, and increased apoptosis in xenograft and PDAC organoid models. Finally, MXRA5, EDIL3, COL13A1, and SLC16A2 were identified as top downstream response genes upon RK-33 treatment, which have been considered potential new targets to mitigate extracellular matrix remodeling, angiogenesis, cell migration, and cell cycle progression, thereby enhancing the therapeutic efficacy of GEM and 5FU. Overall, our data indicate that RK-33 enhances the therapeutic efficacy of GEM and 5FU in mitigating the aggressiveness of PDAC. Consequently, these findings open new avenues for developing efficacious therapeutic adjuvants to treat advanced pancreatic cancer.