Data from Autotaxin Secretion Is a Stromal Mechanism of Adaptive Resistance to TGFβ Inhibition in Pancreatic Ductal Adenocarcinoma

• DOI: 10.1158/0008-5472.c.7002647.v1
• Publication Date: 2024-01-02T08:20:17Z
• Authors: Silvia Pietrobono; Fabio Sabbadini; Monica Bertolini; Domenico Mangiameli; Veronica De Vita; Federica Fazzini; Giulia Lunardi; Simona Casalino; Enza Scarlato; Valeria Merz; Camilla Zecchetto; Alberto Quinzii; Giusy Di Conza; Michael Lahn; Davide Melisi
• Keywords: Autotaxin

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