Publication Date:
2009-09-04
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yauch, Robert L -- Dijkgraaf, Gerrit J P -- Alicke, Bruno -- Januario, Thomas -- Ahn, Christina P -- Holcomb, Thomas -- Pujara, Kanan -- Stinson, Jeremy -- Callahan, Christopher A -- Tang, Tracy -- Bazan, J Fernando -- Kan, Zhengyan -- Seshagiri, Somasekar -- Hann, Christine L -- Gould, Stephen E -- Low, Jennifer A -- Rudin, Charles M -- de Sauvage, Frederic J -- New York, N.Y. -- Science. 2009 Oct 23;326(5952):572-4. doi: 10.1126/science.1179386. Epub 2009 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genentech, South San Francisco, CA 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19726788" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Amino Acid Substitution
;
Anilides/metabolism/pharmacology/*therapeutic use
;
Animals
;
Antineoplastic Agents/metabolism/pharmacology/*therapeutic use
;
Brain Neoplasms/*drug therapy/*genetics/pathology
;
Cell Line, Tumor
;
Cinnamates/pharmacology
;
Drug Resistance, Neoplasm
;
Hedgehog Proteins/antagonists & inhibitors/genetics/*metabolism
;
Humans
;
Medulloblastoma/*drug therapy/*genetics/pathology
;
Mice
;
Molecular Sequence Data
;
Mutant Proteins/antagonists & inhibitors/chemistry/metabolism
;
Mutation, Missense
;
Neoplasm Metastasis
;
Protein Conformation
;
Pyridines/metabolism/pharmacology/*therapeutic use
;
Receptors, Cell Surface/genetics/metabolism
;
Receptors, G-Protein-Coupled/antagonists &
;
inhibitors/chemistry/*genetics/metabolism
;
Signal Transduction
;
Veratrum Alkaloids/pharmacology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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