Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma
Autor: | Thomas Januario, Michael R. Migden, Charles M. Rudin, Frederic J. de Sauvage, Howard Sofen, Peter M. Haverty, Gerrit J. P. Dijkgraaf, Hayley J. Sharpe, Richard Bourgon, Alison B. Durham, Nicole Basset-Seguin, Jean Y. Tang, Luc Dirix, Gregoire Pau, David C. Fisher, Robert L. Yauch, Zora Modrusan, Vickie Tsui, Kavita Y. Sarin, Andrzej A. Dlugosz |
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Rok vydání: | 2014 |
Předmět: |
Models
Molecular Patched Receptors Cancer Research Skin Neoplasms DNA Copy Number Variations Pyridines DNA Mutational Analysis Kruppel-Like Transcription Factors Vismodegib Receptors Cell Surface Drug resistance Biology Zinc Finger Protein Gli2 Bioinformatics Sonidegib Article Receptors G-Protein-Coupled chemistry.chemical_compound GLI2 medicine Humans Basal cell carcinoma Anilides Exome Hedgehog Proteins Hedgehog Binding Sites Nuclear Proteins Cell Biology Sequence Analysis DNA medicine.disease Smoothened Receptor Protein Structure Tertiary Repressor Proteins chemistry Oncology Carcinoma Basal Cell Drug Resistance Neoplasm Mutation Cancer research Human medicine Smoothened medicine.drug |
Zdroj: | Cancer cell |
ISSN: | 1878-3686 1535-6108 |
Popis: | 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. |
Databáze: | OpenAIRE |
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