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<p>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 <i>nab</i>-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.</p>

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Targeting cancer-associated fibroblast-driven LIF/LIFR axis improves the therapeutic efficacy of gemcitabine and nab-paclitaxel in pancreatic cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月22日

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  • Rakesh Bhatia,
  • Imran Khan,
  • Xiaoqi Li,
  • Shailendra Gautam,
  • Parthasarathy Seshacharyulu,
  • Zahraa Wajih Alsafwani,
  • Namita Bhyravbhatla,
  • Moorthy P. Ponnusamy,
  • Maneesh Jain,
  • Mokenge Malafa,
  • Santhamma Bindu,
  • Ahmed Gulzar,
  • Hareesh Nair,
  • Surinder K. Batra,
  • Sushil Kumar

摘要

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.