[Cited FineTest ELISA Kit] Current Research on Pancreatic Cancer

FineTest ELISA kit contributes to the research on pancreatic cancer. The immunoassay is designed to measure Enpp2 concentration in plasma.

Publication Details
Article Title: Autotaxin secretion is a stromal mechanism of adaptive resistance to TGFβ inhibition in pancreatic ductal adenocarcinoma
Journal Title: Cancer Research
DOI: 10.1158/0008-5472.CAN-23-0104
IF: 11.2
PMID: 37738399

Abstract: The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase 2 H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine to gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition. Blocking TGFβ signaling prompted the skewing of cancer associated fibroblasts (CAFs) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin increased LPA-NF-κB signaling in tumor cells that triggered treatment resistance. The autotaxin inhibitor IOA-289 suppressed NF-κB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. In immunocompetent orthotopic murine models, IOA-289 synergized with galunisertib in restoring sensitivity to gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared to those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib.

Keywords: pancreatic cancer, autotaxin, TGFβ receptor inhibitor, drug resistance, cancer associated fibroblasts

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