ArticleMolecular oncology2015
Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma.
Article in Molecular oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 159 citations in OpenAlex.
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- MEVITEM-a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation.Neuro-oncology · 2021Trial
- Sonic Hedgehog-Gli1 signaling promotes microglial activation via the IKKβ/NF-κB pathway.Acta pharmacologica Sinica · 2026Article
- Aberrant Activation of the Hedgehog Pathway in Cutaneous Melanoma: Therapeutic Potential of Pharmacological Inhibitors.International journal of molecular sciences · 2026Article
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- EZH2 inhibitor and Vismodegib synergistically inhibit the growth and metastasis of medulloblastoma.Medical oncology (Northwood, London, England) · 2025Article
- Sonic hedgehog signalling pathway in CNS tumours: its role and therapeutic implications.Molecular brain · 2024Review
- Association of the expression of Bcl-2 and Ki-67 prognostic markers and apoptotic index with biological behaviour in aggressive and non-aggressive non-melanoma eyelid skin cancer.Postepy dermatologii i alergologii · 2024Article
- Systemic Therapy for Non-Melanoma Skin Cancers: Latest Advances.Current oncology reports · 2024Review
- PDLIM3 knockdown promotes ferroptosis in endometriosis progression via inducing Gli1 degradation and blocking Hedgehog signaling pathway.Journal of assisted reproduction and genetics · 2024Article
- Medicinal Chemistry and NMR Driven Discovery of Novel UDP-glucuronosyltransferase 1A Inhibitors That Overcome Therapeutic Resistance in Cells.Journal of molecular biology · 2024Article
- The strategies to cure cancer patients by eradicating cancer stem-like cells.Molecular cancer · 2023Review
- Chemically modified small interfering RNA targeting Hedgehog signaling pathway for rheumatoid arthritis therapy.Molecular therapy. Nucleic acids · 2023Article
- Novel Approaches in Non-Melanoma Skin Cancers-A Focus on Hedgehog Pathway in Basal Cell Carcinoma (BCC).Cells · 2022Review
- Molecular Mechanisms and Targeted Therapies of Advanced Basal Cell Carcinoma.International journal of molecular sciences · 2022Review
- Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer.Journal of personalized medicine · 2022Review
- Long-Term Management of Advanced Basal Cell Carcinoma: Current Challenges and Future Perspectives.Cancers · 2022Review
- Mir-326 potentiates radiosensitivity of cervical squamous cell carcinoma through downregulating SMO expression in the Hedgehog signaling pathway.Genes & genomics · 2022Article
- Noncanonical activation of GLI signaling in SOX2Science advances · 2022Article
19 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Basal cell carcinomas (BCCs) and a subset of medulloblastomas are characterized by loss-of-function mutations in the tumor suppressor gene, PTCH1. PTCH1 normally functions by repressing the activity of the Smoothened (SMO) receptor. Inactivating PTCH1 mutations result in constitutive Hedgehog pathway activity through uncontrolled SMO signaling. Targeting this pathway with vismodegib, a novel SMO inhibitor, results in impressive tumor regression in patients harboring genetic defects in this pathway. However, a secondary mutation in SMO has been reported in medulloblastoma patients following relapse on vismodegib to date. This mutation preserves pathway activity, but appears to confer resistance by interfering with drug binding. Here we report for the first time on the molecular mechanisms of resistance to vismodegib in two BCC cases. The first case, showing progression after 2 months of continuous vismodegib (primary resistance), exhibited the new SMO G497W mutation. The second case, showing a complete clinical response after 5 months of treatment and a subsequent progression after 11 months on vismodegib (secondary resistance), exhibited a PTCH1 nonsense mutation in both the pre- and the post-treatment specimens, and the SMO D473Y mutation in the post-treatment specimens only. In silico analysis demonstrated that SMO(G497W) undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mechanisms leading to primary and secondary resistance to vismodegib, respectively.
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