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Cell Population Analyses During Skin Carcinogenesis
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PTCH/SMO gene mutations in odontogenic keratocysts and drug interventions

Shan Wang1,2, Yingying Hong3, Jiafei Qu4,5

  • 1Department of Basic Science, School of Stomatology, Kunming Medical University, Kunming, China.

Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology
|August 8, 2023
PubMed
Abstract

Insights

Mutations in PTCH1 and SMO genes drive odontogenic keratocyst (OKC) progression. While GDC-0449 effectively targets SHH signaling in some OKCs, GANT61 offers an alternative for resistant cases, including those with specific PTCH1 and SMO mutations.

Area of Science:

  • Oncology
  • Genetics
  • Cell Biology

Background:

  • Odontogenic keratocysts (OKCs) are destructive jaw lesions linked to nevoid basal cell carcinoma syndrome (NBCCS).
  • The precise mechanisms initiating OKC formation and cyst development remain incompletely understood.
  • This study explores the role of PTCH1 and SMO mutations in OKC progression and evaluates sonic hedgehog (SHH) pathway inhibitors.

Purpose of the Study:

  • To investigate the impact of PTCH1 and SMO mutations on OKC fibroblast behavior.
  • To assess the efficacy of SHH signaling pathway inhibitors GDC-0449 and GANT61 in OKC models.

Main Methods:

  • Cultured sporadic and NBCCS-related OKC fibroblasts for in vitro analysis.
  • Utilized EdU, CCK8, and wound-healing assays to examine proliferation and migration.
  • Employed quantitative real-time PCR to assess SHH pathway inhibition by GDC-0449 and GANT61.

Main Results:

  • PTCH1 (c.3499G>A) and SMO (c.2081C>G) mutations enhanced OKC fibroblast proliferation.
  • NBCCS-related OKC fibroblasts with these mutations affected HaCaT cell proliferation and migration.
  • GDC-0449 inhibited SHH signaling in NBCCS-related OKCs with PTCH1 mutations, but resistance was observed with combined PTCH1/SMO mutations, where GANT61 showed efficacy.

Conclusions:

  • Genetic mutations in OKC fibroblasts influence epithelial and stromal cell behavior, contributing to disease.
  • GDC-0449 shows therapeutic potential for OKCs, particularly NBCCS-related types with PTCH1 mutations.
  • SMO mutations may confer resistance to GDC-0449, positioning GANT61 as a viable alternative treatment.
Keywords:
PTCH1 mutationSHH pathway inhibitorSMO mutationodontogenic keratocyst

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