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Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma

Hayley J Sharpe1, Gregoire Pau2, Gerrit J Dijkgraaf1

  • 1Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.

Cancer Cell
|March 12, 2015
PubMed

Insights

Vismodegib resistance in basal cell carcinoma (BCC) is linked to Hedgehog (Hh) pathway reactivation, often via SMO mutations. Combination therapies targeting multiple Hh pathway components may overcome this resistance.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Smoothened (SMO) inhibitors, like vismodegib, are used for basal cell carcinoma (BCC).
  • While effective, some BCC patients develop resistance to vismodegib.
  • Understanding resistance mechanisms is crucial for improving cancer treatment.

Purpose of the Study:

  • To investigate the genomic basis of vismodegib resistance in BCC.
  • To identify key molecular alterations driving Hedgehog (Hh) pathway reactivation.
  • To inform the development of strategies to overcome treatment resistance.

Main Methods:

  • Genomic analysis of tumor biopsies from BCC patients.
  • Identification of mutations and copy number changes in key pathway genes.
  • Correlation of genomic alterations with vismodegib resistance.

Main Results:

  • Vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation.
  • Predominant mechanism is SMO mutation, impairing drug binding or activating SMO.
  • Secondary mechanisms include SUFU and GLI2 copy number changes.
  • Evidence of intra-tumor heterogeneity in resistance mechanisms.

Conclusions:

  • SMO mutations are a primary driver of vismodegib resistance in BCC.
  • Hedgehog (Hh) pathway reactivation underlies treatment failure.
  • Combination therapies targeting multiple Hh pathway levels are needed to overcome resistance.

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