Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell Carcinoma Academic Article uri icon

Overview

MeSH Major

  • Anilides
  • Carcinoma, Basal Cell
  • Drug Resistance, Neoplasm
  • Pyridines
  • Receptors, G-Protein-Coupled
  • Skin Neoplasms

abstract

  • 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.

publication date

  • January 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2015.02.001

PubMed ID

  • 25759019

Additional Document Info

start page

  • 327

end page

  • 41

volume

  • 27

number

  • 3