A Novel TGF-β Trap Blocks Chemotherapeutics-Induced TGF-β1 Signaling and Enhances Their Anticancer Activity in Gynecological Cancers.

Purpose: We investigated the mechanisms of how TGF beta pathway is activated by chemotherapeutics and whether a novel TGF beta trap called RER can block chemotherapeutics-induced TGF beta pathway activation and enhance their antitumor activity in gynecologic cancer. Patients and Methods: An unbiased bioinformatic analysis of differentially expressed genes in 31 ovarian cases due to chemotherapy was used to identify altered master regulators. Phosphorylated Smad2 was determined in 30 paired cervical cancer using IHC. Furthermore, the effects of chemotherapeutics on TGF beta signaling and function, and the effects of RER on chemotherapy-induced TGF beta signaling were determined in gynecologic cancer cells. Results: Chemotherapy-induced transcriptome alteration in ovarian cancer was significantly associated with TGF beta signaling activation. Chemotherapy was found to activate TGF beta signaling as indicated by phosphorylated Smad2 in paired cervical tumor samples (pre- and post-chemotherapy). Similar to TGF beta 1, chemotherapeutics were found to stimulate Smad2/3 phosphorylation, cell migration, and markers related to epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC). These TGF beta-like effects were due to the stimulation of TGF beta 1 expression and secretion, and could all be abrogated by TGF beta inhibitors including a novel TGF beta trap protein called RER both in vitroand invivo Importantly, combination treatment with RER and cisplatin showed a higher tumor inhibitory activity than either agent alone in a xenograft model of ovarian cancer. Conclusions: Chemotherapeutics can stimulate TGF beta 1 production and consequently enhance TGF beta signaling, EMT, and CSC features resulting in reduced chemo-sensitivity. Combination therapy with a TGF beta inhibitor should alleviate this unintended side effect of chemotherapeutics and enhance their therapeutic efficacy. (C) 2018 AACR.