Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma Journal Article
| Authors: | Sharpe, H. J.; Pau, G.; Dijkgraaf, G. J.; Basset-Seguin, N.; Modrusan, Z.; Januario, T.; Tsui, V.; Durham, A. B.; Dlugosz, A. A.; Haverty, P. M.; Bourgon, R.; Tang, J. Y.; Sarin, K. Y.; Dirix, L.; Fisher, D. C.; Rudin, C. M.; Sofen, H.; Migden, M. R.; Yauch, R. L.; De Sauvage, F. J. |
| Article Title: | Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma |
| 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 BCCpatients 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. © 2015 Elsevier Inc. |
| Keywords: | clinical article; controlled study; human tissue; gene mutation; human cell; nonhuman; mouse; gene; basal cell carcinoma; animal experiment; animal model; cancer resistance; molecular mechanics; genomics; erinaceidae; vismodegib; smo gene; human; priority journal; article; ptch1 gene |
| Journal Title: | Cancer Cell |
| Volume: | 27 |
| Issue: | 3 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2015-03-09 |
| Start Page: | 327 |
| End Page: | 341 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2015.02.001 |
| PROVIDER: | scopus |
| PUBMED: | 25759019 |
| PMCID: | PMC5675004 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
