journal contribution
posted on 2024-01-02, 08:20 authored by 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 Figures S1-5, Tables S1-3
Funding
Associazione Nastro Viola
Associazione Voglio il Massimo
Fondazione AIRC per la ricerca sul cancro ETS (AIRC)
Ministero della Salute (Italy Ministry of Health)
Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR)
History
ARTICLE ABSTRACT
The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase II H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine with 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 (CAF) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin increased LPA-NFκB signaling in tumor cells that triggered treatment resistance. The autotaxin inhibitor IOA-289 suppressed NFκB 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 with 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.
TGFβ inhibition skews cancer-associated fibroblasts toward an inflammatory phenotype that secretes autotaxin to drive adaptive resistance in PDAC, revealing autotaxin as a therapeutic target and biomarker of galunisertib response.
