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.

Tongue and Taste Organ Biology and Function: Homeostasis Maintained by Hedgehog Signaling

“…Hedgehog pathway inhibition (HPI) at the Smo receptor has also been studied with a pharmacologic block by the drugs LDE225 or Vismodegib (83, 84) (see Section 10). After oral gavage in mice for 16–28 days, the number of intact FGP and taste buds is essentially eliminated (83).…”

Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma

“…Pathway inhibition impairs production of angiogenic factors, decreases muscle blood flow, and reduces capillary density after injury [19]. Hedgehog signaling has been shown to regulate development and maintenance of taste buds and seems to play a critical role in taste function integrity [20, 21]. Adult mice treated with vismodegib display significant reductions in taste-bud size and number of taste cells, and decreased behavioral responses to sweet and bitter stimuli [21].…”

“…Hedgehog signaling has been shown to regulate development and maintenance of taste buds and seems to play a critical role in taste function integrity [20, 21]. Adult mice treated with vismodegib display significant reductions in taste-bud size and number of taste cells, and decreased behavioral responses to sweet and bitter stimuli [21]. Interestingly, hedgehog-responding cells were lost in fungiform papilla epithelium in sonidegib-treated mice, with taste-bud remnants entirely absent or severely decreased in >90% of aberrant papillae [22].…”

“…Vismodegib decreases the number of Shh-expressing type IV taste cells [21], which have been shown to be critical for taste-bud differentiation in adults. Taste disturbances occur in 50%–71% of vismodegib-treated patients, typically developing within the first few months of treatment (Table 2).…”

Dysgeusia and weight loss under treatment with vismodegib: benefit of nutritional management

“…Cancer chemotherapyinduced dysgeusia seems to be responsible for a reduction in food intake [14], resulting in weight loss and malnutrition. Yang et al [15] investigated the effects of vismodegib given orally to mice: vismodegib administration led to decreased body weight and reduction in the number of cells expressing taste receptors. In our Nutrition cohort, two patients without dysgeusia (among a total of six patients without dysgeusia in this cohort) experienced a weight loss greater than 5 % under vismodegib.…”