Title
Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
Cambridge, Mass. ,
Subject
Biology
Human medicine
Source (journal)
Cancer cell. - Cambridge, Mass.
Volume/pages
27(2015) :3 , p. 327-341
ISSN
1535-6108
ISI
000350977200006
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
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