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Updated: Jun 20, 2026
Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
Published on: September 1, 2010
Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma
Robert L Yauch1, Gerrit J P Dijkgraaf, Bruno Alicke
1Genentech, South San Francisco, CA 94080, USA.
Abstract:
The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein-coupled receptor can serve as a mechanism of drug resistance in human cancer.
Insights
Drug resistance in medulloblastoma can occur when mutations in the Smoothened (SMO) receptor prevent cancer drugs from binding. This study identified a specific SMO mutation causing resistance to Hedgehog pathway inhibitors like GDC-0449.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The Hedgehog (Hh) signaling pathway is crucial for development but its aberrant activation drives certain cancers, notably medulloblastoma.
- GDC-0449, a Smoothened (SMO) inhibitor, shows efficacy in Hh-driven cancers, but resistance mechanisms require elucidation.
Purpose of the Study:
- To investigate the molecular mechanisms of acquired resistance to GDC-0449 in a medulloblastoma patient.
- To identify specific genetic alterations in the Hedgehog pathway conferring drug resistance.
Main Methods:
- Analysis of tumor samples from a medulloblastoma patient who relapsed on GDC-0449 therapy.
- Determination of the mutational status of Hedgehog signaling pathway genes.
- Assessment of drug-target interactions and pathway activity.
Main Results:
- A novel amino acid substitution in the Smoothened (SMO) receptor was identified in the resistant tumor.
- This SMO mutation impaired GDC-0449 binding and Hh pathway inhibition without affecting basal Hh signaling.
- A similar SMO mutation was observed in a GDC-0449-resistant medulloblastoma mouse model.
Conclusions:
- Acquired mutations in the Smoothened (SMO) receptor represent a key mechanism of resistance to Hedgehog pathway inhibitors in medulloblastoma.
- Understanding these resistance mutations is critical for developing strategies to overcome therapeutic failure in Hh-driven cancers.
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