Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma

Cancer Cell. 2015 Mar 9;27(3):327-41. doi: 10.1016/j.ccell.2015.02.001.


Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.

MeSH terms

  • Anilides / chemistry
  • Anilides / therapeutic use*
  • Binding Sites
  • Carcinoma, Basal Cell / drug therapy
  • Carcinoma, Basal Cell / genetics*
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm / genetics*
  • Exome
  • Hedgehog Proteins / genetics
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Models, Molecular
  • Mutation
  • Nuclear Proteins / genetics
  • Patched Receptors
  • Protein Structure, Tertiary
  • Pyridines / chemistry
  • Pyridines / therapeutic use*
  • Receptors, Cell Surface / genetics
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / genetics*
  • Repressor Proteins / genetics
  • Sequence Analysis, DNA
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics*
  • Smoothened Receptor
  • Zinc Finger Protein Gli2


  • Anilides
  • GLI2 protein, human
  • Hedgehog Proteins
  • HhAntag691
  • Kruppel-Like Transcription Factors
  • Nuclear Proteins
  • Patched Receptors
  • Pyridines
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Repressor Proteins
  • SMO protein, human
  • SUFU protein, human
  • Smoothened Receptor
  • Zinc Finger Protein Gli2