Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell Carcinoma

Hayley J. Sharpe, Gregoire Pau, Gerrit J. Dijkgraaf, Nicole Basset-Seguin, Zora Modrusan, Thomas Januario, Vickie Tsui, Alison B. Durham, Andrzej A. Dlugosz, Peter M. Haverty, Richard Bourgon, Jean Y. Tang, Kavita Y. Sarin, Luc Dirix, David C. Fisher, Charles M. Rudin, Howard Sofen, Michael R. Migden, Robert L. Yauch, Frederic J. de Sauvage

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)327-341
Number of pages15
JournalCancer Cell
Volume27
Issue number3
DOIs
StatePublished - Mar 9 2015
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology
  • Medicine(all)

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    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. (2015). Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell Carcinoma. Cancer Cell, 27(3), 327-341. https://doi.org/10.1016/j.ccell.2015.02.001