TGFβ受体抑制剂加卢尼塞替在随机2期H9H-MC-JBAJ研究中表现出对胰管腺癌（PDAC）患者的疗效，该研究比较了加卢尼塞替与化疗药物吉西他滨（gemcitabine）和仅使用吉西他滨的效果。然而，额外的基质旁分泌信号可能会导致适应性耐药性，限制了这种治疗策略的疗效。在这里，我们发现一种分泌酶自动分泌素（autotaxin，ATX），它通过生成溶血磷酸甘油酸（lysophosphatidic acid，LPA）来促进炎症和纤维化，并介导了对TGFβ受体抑制的适应性耐药性。阻断TGFβ信号传导使癌相关成纤维细胞（CAFs）倾向于发炎（iCAF）表型。iCAFs负责大量分泌自动分泌素。旁分泌的自动分泌素增加了磷酸甘油酸-核因子κB（LPA-NF-κB）信号转导在肿瘤细胞中的增加，并触发治疗耐药性。自动分泌素抑制剂IOA-289抑制了PDAC细胞中的NF-κB激活，并克服了加卢尼塞替和吉西他滨的耐药性。在免疫复合原位小鼠模型中，IOA-289与加卢尼塞替协同作用，恢复了对吉西他滨的敏感性。最重要的是，与加卢尼塞替治疗前相比，加卢尼塞替治疗后血浆自动分泌素水平显著增加在H9H-MC-JBAJ研究中入组患者中，没有自动分泌素增加的患者的中位无进展生存期显著延长。这些结果表明，CAF分泌的自动分泌素通过TGFβ抑制增加，循环的自动分泌素水平可以预测加卢尼塞替与吉西他滨联合治疗的疗效。

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.