Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma Academic Article uri icon

Overview

MeSH Major

  • Anilides
  • Antineoplastic Agents
  • Brain Neoplasms
  • Hedgehog Proteins
  • Medulloblastoma
  • Pyridines
  • Receptors, G-Protein-Coupled

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.

publication date

  • October 23, 2009

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5310713

Digital Object Identifier (DOI)

  • 10.1126/science.1179386

PubMed ID

  • 19726788

Additional Document Info

start page

  • 572

end page

  • 4

volume

  • 326

number

  • 5952