GDC-0449 suppresses odontogenic keratocyst aggressiveness in fibroblasts by upregulating SPARC via Hedgehog pathway inhibition PMID: 40840062

ADC Targets in Oncology

2026-04-10

GDC-0449 suppresses odontogenic keratocyst aggressiveness in fibroblasts by upregulating SPARC via Hedgehog pathway inhibition

Arch Oral Biol. 2025 Aug 13:179:106374. doi: 10.1016/j.archoralbio.2025.106374.

Jiafei Qu ¹ , Yongqi Jiang ² , Shian Wu ³ , Xiwen Chen ⁴ , Jiemei Zhai ⁵ , Jing Gao ⁶ , Yuanzhu Zhou ⁷ , Yingying Hong ⁸ , Jing Shen ⁹ , Defu Chen ¹⁰

Affiliations

1. Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin 300041, China. Electronic address: [email protected].
2. College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: [email protected].
3. College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: [email protected].
4. College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: [email protected].
5. Department of Basic Science, School of Stomatology, Kunming Medical University, Kunming 650500, China. Electronic address: [email protected].
6. Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin 300041, China. Electronic address: [email protected].
7. Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin 300041, China. Electronic address: [email protected].
8. First Clinical Division, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China. Electronic address: [email protected].
9. Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin 300041, China. Electronic address: [email protected].
10. College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: [email protected].

Abstract

Objective: Odontogenic keratocysts (OKCs) are aggressive jaw lesions, either linked to Gorlin-Goltz syndrome or sporadic. We aimed to investigate the impact of the Hedgehog (Hh) pathway inhibitor GDC-0449 on OKC fibroblasts (OKC-Fs). Additionally, we explored whether secreted protein acidic and rich in cysteine (SPARC) was a novel Hh target and its association with OKC aggressiveness.

Design: Fibroblasts from four syndromic and four non-syndromic OKCs were isolated, with patched 1 (PTCH1) mutations found only in syndromic ones. Syndromic OKC-Fs with PTCH1 mutations were treated with GDC-0449, using mutation-free non-syndromic OKC-Fs as controls. Wound healing and transwell assays assessed the migration and invasion of OKC-Fs. Real-time polymerase chain reaction (PCR), Alkaline Phosphatase staining, and tartrate-resistant Acid Phosphatase staining investigated osteogenic differentiation and osteoclastogenic effects. Real-Time PCR and western blotting examined the correlation between SPARC and Hh signaling. SPARC siRNA treatment tested its effect on cell migration and invasion.

Results: GDC-0449 inhibited the migration, invasion, and osteoclastogenic ability, while promoting their osteogenic differentiation of syndromic OKC-Fs. Moreover, GDC-0449 inhibited Hh pathway by decreasing glioma-associated oncogene 1 (GLI1) expression in syndromic OKC-Fs harboring PTCH1 mutations. Additionally, by suppressing Hh pathway, GDC-0449 upregulated SPARC expression, suggesting that Hh-GLI1 signaling exerts a negative regulatory effect on SPARC. Knockdown of SPARC promoted the migration and invasion of OKC-Fs, which could be reversed by GDC-0449.

Conclusion: GDC-0449 suppresses aggressiveness and osteoclastogenesis of OKCs while promoting osteogenesis. GDC-0449 treats OKCs by inhibiting Hh signaling and upregulating SPARC. SPARC could be a potential therapeutic target for OKCs.

Keywords

Hh pathway inhibitor; Invasion; Migration; Odontogenic keratocyst; PTCH1 mutation; SPARC.