Iloprost requires the Frizzled-9 receptor to prevent lung cancer
Kayla Sompel, Lori D. Dwyer‐Nield, Alex J. Smith, Alamelu P. Elango, Don S. Backos, Bicheng Zhang, James Gross, Kristina Ternyak, Jennifer L. Matsuda, Katrina W. Kopf, Robert L. Keith, Meredith A. Tennis
Abstract
Prevention of premalignant lesion progression is a promising approach to reducing lung cancer burden in high-risk populations. Substantial preclinical and clinical evidence has demonstrated efficacy of the prostacyclin analogue iloprost for lung cancer chemoprevention. Iloprost activates peroxisome proliferator-activated receptor gamma (PPARG) to initiate chemopreventive signaling and in vitro, which requires the transmembrane receptor Frizzled9 (FZD9). We hypothesized a Fzd9−/− mouse would not be protected by iloprost in a lung cancer model. Fzd9−/− mice were treated with inhaled iloprost in a urethane model of lung adenoma. We found that Fzd9−/− mice treated with iloprost were not protected from adenoma development compared to wild-type mice nor did they demonstrate increased activation of iloprost signaling pathways. Our results established that iloprost requires FZD9 in vivo for lung cancer chemoprevention. This work represents a critical advancement in defining iloprost’s chemopreventive mechanisms and identifies a potential response marker for future clinical trials.