| Literature DB >> 25759019 |
Hayley J Sharpe1, Gregoire Pau2, Gerrit J Dijkgraaf1, Nicole Basset-Seguin3, Zora Modrusan4, Thomas Januario1, Vickie Tsui5, Alison B Durham6, Andrzej A Dlugosz6, Peter M Haverty2, Richard Bourgon2, Jean Y Tang7, Kavita Y Sarin7, Luc Dirix8, David C Fisher9, Charles M Rudin10, Howard Sofen11, Michael R Migden12, Robert L Yauch1, Frederic J de Sauvage13.
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.Entities:
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Year: 2015 PMID： 25759019 PMCID： PMC5675004 DOI： 10.1016/j.ccell.2015.02.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743