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Recovery of taste organs and sensory function after severe loss from Hedgehog/Smoothened inhibition with cancer drug sonidegib

  1. Charlotte M. Mistrettaa,1,2
  1. aDepartment of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109;
  2. bDepartment of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109;
  3. cDepartment of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109
  1. Edited by Linda M. Bartoshuk, University of Florida, Gainesville, FL, and approved October 11, 2017 (received for review July 19, 2017)

Significance

Hedgehog pathway-inhibitor drugs effectively treat basal cell carcinoma, a common skin cancer. However, many patients taking such drugs report severe taste disturbances that impair their quality of life. To understand the biology behind these adverse effects, we studied the consequences of Hedgehog pathway inhibition on taste organs and neural sensation in mice. Taste bud progenitor-cell proliferation and differentiation were altered, resulting in taste bud loss. Nerve responses to lingual taste stimuli were also eliminated, while responses to touch and cold stimuli remained. After stopping Hedgehog pathway inhibition, taste buds and sensory responses recovered. This study advances our understanding of Hedgehog signaling in taste homeostasis and the reported taste recovery after clinical treatments with Hedgehog pathway-inhibiting drugs.

Abstract

Striking taste disturbances are reported in cancer patients treated with Hedgehog (HH)-pathway inhibitor drugs, including sonidegib (LDE225), which block the HH pathway effector Smoothened (SMO). We tested the potential for molecular, cellular, and functional recovery in mice from the severe disruption of taste-organ biology and taste sensation that follows HH/SMO signaling inhibition. Sonidegib treatment led to rapid loss of taste buds (TB) in both fungiform and circumvallate papillae, including disruption of TB progenitor-cell proliferation and differentiation. Effects were selective, sparing nontaste papillae. To confirm that taste-organ effects of sonidegib treatment result from HH/SMO signaling inhibition, we studied mice with conditional global or epithelium-specific Smo deletions and observed similar effects. During sonidegib treatment, chorda tympani nerve responses to lingual chemical stimulation were maintained at 10 d but were eliminated after 16 d, associated with nearly complete TB loss. Notably, responses to tactile or cold stimulus modalities were retained. Further, innervation, which was maintained in the papilla core throughout treatment, was not sufficient to sustain TB during HH/SMO inhibition. Importantly, treatment cessation led to rapid and complete restoration of taste responses within 14 d associated with morphologic recovery in about 55% of TB. However, although taste nerve responses were sustained, TB were not restored in all fungiform papillae even with prolonged recovery for several months. This study establishes a physiologic, selective requirement for HH/SMO signaling in taste homeostasis that includes potential for sensory restoration and can explain the temporal recovery after taste dysgeusia in patients treated with HH/SMO inhibitors.

Footnotes

  • ?1A.A.D., B.L.A., R.M.B., and C.M.M. contributed equally to this work.

  • ?2To whom correspondence should be addressed. Email: chmist{at}umich.edu.
  • Author contributions: A.K., A.N.E., A.A.D., B.L.A., R.M.B., and C.M.M. designed research; A.K., A.N.E., R.M.B., and C.M.M. performed research; M.G. contributed new reagents/analytic tools; A.K., A.N.E., A.A.D., B.L.A., R.M.B., and C.M.M. analyzed data; and A.K., A.A.D., B.L.A., R.M.B., and C.M.M. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1712881114/-/DCSupplemental.

Published under the PNAS license.

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