Targeting stromal Autotaxin synergizes with TGFb inhibition in modulating pancreatic cancer chemoresistance

Galunisertib, a TGFb receptor (TbR) inhibitor, showed, when combined with standard chemotherapy, a strong efficacy for the treatment of pancreatic ductal adenocarcinoma (PDAC) patients. This efficacy was also due to the modulation of stromal microenvironment. However, several alternative pathways, that are capable to induce cancer cells survival via stromal paracrine signals in response to chemotherapy arise, limiting the efficacy of the pharmacological inhibition of TbR. The enzymatic role of autotaxin (Atx) is to convert lysophosphatidylcholine (LPC) into its bioactive lipid called lysophosphatidic acid (LPA). LPA, in turn, promotes both fibrosis and inflammation, playing a fundamental role in the chemoresistance of the disease. Pharmacological inhibition of Atx with a novel Atx inhibitor (IOA- 289) is indicated in the treatment of tumor characterized by a high degree of fibrosis and stromal involvement. We used several murine PDAC orthotopic models in order to unveil a new Atx-mediated mechanism of adaptive response to pharmacological inhibition of TbR. We demonstrated that TbR inhibition induces Atx upregulation promoting the activation of Nf-kb-Cxcl1 axis, which is implicated in therapy resistance. We also showed that inhibition of Atx-LPA axis using IOA- 289 combined with TbR inhibition using galunisertib yields to a synergistic effect that increases the sensitivity of PDAC cells to chemotherapy. Combined therapy also reduces the degree of fibrosis and promotes tumor infiltration of cytotoxic T lymphocytes. Moreover, the group of mice receiving IOA-289 plus galunisertib in combination with gemcitabine displays the longest survival when compared to mice groups treated with any double pharmacological combination [mOS=47 days, p<0.05]. In conclusion, we recommend IOA-289 as a new treatment in combination with galunisertib and gemcitabine for the treatment of PDAC patients characterized by an extended desmoplasia.