Targeting cancer-associated fibroblast-driven LIF/LIFR axis improves the therapeutic efficacy of gemcitabine and nab-paclitaxel in pancreatic cancer
Rick Bhatia, Imran Khan, Xiaoqi Li, Shailendra K. Gautam, Parthasarathy Seshacharyulu, Zahraa Wajih Alsafwani, Namita Bhyravbhatla, Moorthy P. Ponnusamy, Maneesh Jain, Mokenge P. Malafa, S. Hima Bindu, Ahmed Gulzar, Hareesh B. Nair, Surinder K. Batra, Sushil Kumar
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.