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Recovery of taste organs and sensory function after severe loss from Hedgehog/Smoothened inhibition with cancer drug sonidegib.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Nov 28; Vol. 114 (48), pp. E10369-E10378. Date of Electronic Publication: 2017 Nov 13. - Publication Year :
- 2017
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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.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Animals
Carcinoma, Basal Cell drug therapy
Cell Differentiation drug effects
Cell Proliferation drug effects
Chorda Tympani Nerve drug effects
Chorda Tympani Nerve physiopathology
Disease Models, Animal
Dysgeusia chemically induced
Dysgeusia pathology
Hedgehog Proteins antagonists & inhibitors
Hedgehog Proteins metabolism
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Recovery of Function
Skin Neoplasms drug therapy
Smoothened Receptor antagonists & inhibitors
Smoothened Receptor genetics
Smoothened Receptor metabolism
Stem Cells drug effects
Taste physiology
Taste Buds cytology
Taste Buds drug effects
Taste Buds pathology
Taste Buds physiopathology
Tongue drug effects
Tongue innervation
Antineoplastic Agents adverse effects
Biphenyl Compounds adverse effects
Dysgeusia physiopathology
Pyridines adverse effects
Signal Transduction drug effects
Taste drug effects
Tongue physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 114
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 29133390
- Full Text :
- https://doi.org/10.1073/pnas.1712881114