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Vismodegib resistance in basal cell carcinoma: not a smooth fit

Todd W Ridky1, George Cotsarelis1

  • 1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, BRB 1053, 421 Curie Boulevard, Philadelphia, PA 19104, USA.

Cancer Cell
|March 12, 2015
PubMed

Insights

Basal cell carcinomas resistant to vismodegib often have Smoothened (SMO) mutations. These mutations can reduce drug binding or increase basal SMO activity, contributing to treatment resistance.

Area of Science:

  • Oncology
  • Dermatology
  • Molecular Biology

Background:

  • Basal cell carcinoma (BCC) is the most common human cancer.
  • Vismodegib, a Smoothened (SMO) inhibitor, is a targeted therapy for advanced BCC.
  • Treatment resistance to vismodegib is a significant clinical challenge.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying vismodegib resistance in basal cell carcinoma.
  • To identify specific mutations in the Smoothened (SMO) gene associated with treatment failure.

Main Methods:

  • Analysis of tumor samples from patients with vismodegib-resistant BCC.
  • Genomic sequencing to identify mutations in the SMO gene.
  • Functional assays to assess the impact of SMO mutations on drug binding and signaling.

Main Results:

  • Vismodegib-resistant BCC frequently harbors mutations in the SMO gene.
  • Specific SMO mutations were found to limit the binding of vismodegib.
  • Certain SMO mutations were also observed to increase basal SMO pathway activity, independent of drug inhibition.

Conclusions:

  • SMO mutations are a key mechanism of acquired resistance to vismodegib in basal cell carcinoma.
  • Understanding these mutations can inform the development of next-generation therapies.
  • Targeting the SMO pathway remains a critical strategy for BCC treatment.

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