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

doi:10.1016/j.ccell.2015.02.001

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 journal › Article › peer-review

209 Scopus citations

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 language	English (US)
Pages (from-to)	327-341
Number of pages	15
Journal	Cancer Cell
Volume	27
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2015.02.001
State	Published - Mar 9 2015
Externally published	Yes

ASJC Scopus subject areas

Cancer Research
Cell Biology
Oncology
General Medicine

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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

Sharpe, HJ, Pau, G, Dijkgraaf, GJ, Basset-Seguin, N, Modrusan, Z, Januario, T, Tsui, V, Durham, AB, Dlugosz, AA, Haverty, PM, Bourgon, R, Tang, JY, Sarin, KY, Dirix, L, Fisher, DC, Rudin, CM, Sofen, H, Migden, MR, Yauch, RL & de Sauvage, FJ 2015, 'Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell Carcinoma', Cancer Cell, vol. 27, no. 3, pp. 327-341. https://doi.org/10.1016/j.ccell.2015.02.001

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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.",

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

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AU - Sharpe, Hayley J.

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AU - Dijkgraaf, Gerrit J.

AU - Basset-Seguin, Nicole

AU - Modrusan, Zora

AU - Januario, Thomas

AU - Tsui, Vickie

AU - Durham, Alison B.

AU - Dlugosz, Andrzej A.

AU - Haverty, Peter M.

AU - Bourgon, Richard

AU - Tang, Jean Y.

AU - Sarin, Kavita Y.

AU - Dirix, Luc

AU - Fisher, David C.

AU - Rudin, Charles M.

AU - Sofen, Howard

AU - Migden, Michael R.

AU - Yauch, Robert L.

AU - de Sauvage, Frederic J.

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AB - 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.

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Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell Carcinoma

Abstract

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