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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., Significance: 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., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: Pancreatic cancer is one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We identified TAK1 as a central hub sustaining this resistance. Nanoliposomal irinotecan (nal-IRI) is a novel treatment for metastatic gemcitabine-refractory pancreatic cancer. We endeavored to identify circulating markers for TAK1 activation predicting chemoresistance in this setting., Experimental Design: In vivo activity of nal-IRI was validated in an orthotopic nude murine model expressing TAK1-specific shRNA. Plasma concentration of 20 different cytokines were measured by a multiplex xMAP/Luminex technology in patients prospectively enrolled to receive nal-IRI plus 5-fluorouracil/leucovorin (5-FU/LV). The optimal cutoff thresholds able to significantly predict patients' outcome were obtained on the basis of the maximization of the Youden's statistics., Results: Differential expression profiling revealed the gene coding for IL8 as the most significantly downregulated in shTAK1 pancreatic cancer cell lines. Mice bearing shTAK1 tumors had significantly lower plasma levels of IL8 and experienced a significant reduction in tumor growth if treated with nal-IRI, whereas those bearing TAK1-proficient tumors were resistant to this agent. In a discovery cohort of 77 patients, IL8 was the circulating factor most significantly correlated with survival (plasma levels lower vs higher than cutoff: mPFS 3.4 months vs 2.8 months; hazard ratio [HR], 2.55; 95% CI, 1.39-4.67; P = 0.0017; median overall survival 8.9 months vs 5.3 months; HR, 3.51; 95% CI, 0.84-6.68; P = 4.9e-05). These results were confirmed in a validation cohort of 50 patients., Conclusions: Our study identified IL8 as the most significant circulating factor for TAK1 pathway activation and candidates IL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory patients with pancreatic cancer., (©2020 American Association for Cancer Research.)