Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds

Abstract

Vismodegib, a highly selective inhibitor of hedgehog (Hh) pathway, is an approved treatment for basal-cell carcinoma. Patients on treatment with vismodegib often report profound alterations in taste sensation. The cellular mechanisms underlying the alterations have not been studied. Sonic Hh (Shh) signaling is required for cell growth and differentiation. In taste buds, Shh is exclusively expressed in type IV taste cells, which are undifferentiated basal cells and the precursors of the three types of taste sensing cells. Thus, we investigated if vismodegib has an inhibitory effect on taste cell turnover because of its known effects on Hh signaling. We gavaged C57BL/6J male mice daily with either vehicle or 30 mg/kg vismodegib for 15 weeks. The gustatory behavior and immunohistochemical profile of taste cells were examined. Vismodegib-treated mice showed decreased growth rate and behavioral responsivity to sweet and bitter stimuli, compared to vehicle-treated mice. We found that vismodegib-treated mice had significant reductions in taste bud size and numbers of taste cells per taste bud. Additionally, vismodegib treatment resulted in decreased numbers of Ki67- and Shh-expressing cells in taste buds. The numbers of phospholipase Cβ2- and α-gustducin-expressing cells, which contain biochemical machinery for sweet and bitter sensing, were reduced in vismodegib-treated mice. Furthermore, vismodegib treatment resulted in reduction in numbers of T1R3, glucagon-like peptide-1, and glucagon-expressing cells, which are known to modulate sweet taste sensitivity. These results suggest that inhibition of Shh signaling by vismodegib treatment directly results in alteration of taste due to local effects in taste buds. Vismodegib, an inhibitor of hedgehog (hh) signaling, is the first oral medicine approved by the US Food and Drug Administration for the treatment of adults with advanced basal-cell carcinoma and, interestingly, patients on vismodegib treatment often report distortion in taste perception (dysgeusia). The processing of taste begins with molecular events at the surface membrane of modified epithelial-derived taste cells and sonic hh (Shh) plays a critical role in development and maintaining of taste papillae in rodents. In this study, we demonstrate that vismodegib treatment causes alteration in taste cell turnover and expression of taste sensing machinery in taste cells, suggesting that inhibition of Shh signaling by vismodegib treatment directly results in alteration of taste due to local effects in taste buds.