Abstract C18: TGF-beta blockade paradoxically activates non-SMAD signaling

Abstract

Abstract Transforming growth factor-beta (TGF-B) activates a receptor leading to a critical signaling cascade in pancreatic ductal adenocarcinoma (PDAC) that results in cancer progression through epithelial-to-mesenchymal transition (EMT) and therapeutic resistance. This signaling is through both the canonical SMAD and non-SMAD proteins. Clinically, there exists a TGF-B paradox where TGF-B is a tumor suppressor in nonmetastatic PDAC but a tumor promotor in metastatic PDAC. We hypothesized that TGF-B receptor blockade helps explain the paradox leading to EMT and therapeutic resistance due to non-SMAD signaling. We investigated expression of proteins involved in non-SMAD TGF-B signaling in human PDAC cell lines with Western blot and in patient-derived organoids with immunofluorescence. Inhibition of the TGF-B receptor type 1 with galunisertib resulted in increased phospho-MAPK14 and phospho-Akt compared to controls. In metastatic PDAC, we also demonstrated that this results in increased levels of the activate beta-catenin complex. There were no changes to SMAD2 or SMAD3 phosphorylation. Our work demonstrates that despite blocking of the TGF-B receptor 1, phosphorylation of MAPK14 increases leading to non-SMAD signaling through Akt. Our data demonstrate that beta-catenin is the effector molecule for cancer progression. Our results also demonstrate a possible mechanism for the development of therapeutic resistance in patients with PDAC who undergo TGF-B receptor inhibition therapy. Citation Format: S. Mazher Husain, Rita Kansal, Marcus A. Alvarez, Evan S. Glazer. TGF-beta blockade paradoxically activates non-SMAD signaling [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C18.