Document Type
Article
Journal Title
NPJ Precision Oncology
Publication Date
2025
Volume
9
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is inherently therapy resistant due to cancer cell-stroma crosstalk across several signaling pathways. Among these, the LIF/LIFR axis has been implicated in cancer cell and cancer-associated fibroblast (CAF) crosstalk. We evaluated the efficacy of EC359, a competitive inhibitor of LIFR, in combination with gemcitabine. EC359 reduced tumor burden by 90% compared to controls and by 55% compared to gemcitabine alone in cancer cell and CAFs co-implannation model. The RNA-seq analysis revealed a significant alteration in extracellular matrix components, stemness, microtubule assembly, and immune response, suggesting simultaneous targeting of cancer cell-intrinsic and stroma-mediated mechanisms by EC359. In autochthonous murine model of PDAC, EC359 enhanced the therapeutic efficacy of gemcitabine and nab-paclitaxel, accompanied by an increase in dendritic cells but a reduction in T-regulatory cells. Thus, EC359 reduces PDAC cell stemness, stabilizes microtubule assembly, and reduces the immunosuppressive microenvironment to improve the efficacy of standard-of-care in PDAC.
ISSN
2397-768X
DOI Link
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Recommended Citation
Bhatia, Rakesh; Khan, Imran; Li, Xiaoqi; Gautam, Shailendra; Seshacharyulu, Parthasarathy; Alsafwani, Zahraa Wajih; Bhyravbhatla, Namita; Ponnusamy, Moorthy P.; Jain, Maneesh; Malafa, Mokenge; Bindu, Santhamma; Gulzar, Ahmed; Nair, Hareesh; Batra, Surinder K.; and Kumar, Sushil, "Targeting Cancer-Associated Fibroblast-Driven LIF/LIFR Axis Improves the Therapeutic Efficacy of Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer" (2025). Journal Articles: Biochemistry & Molecular Biology. 177.
https://digitalcommons.unmc.edu/com_bio_articles/177