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

Cancer Cell. 2015 Mar 9;27(3):327-41. doi: 10.1016/j.ccell.2015.02.001.

Authors

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

Affiliations

¹ Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.
² Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
³ Paris 7 Hôpital Saint-Louis, Paris 75010, France.
⁴ Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
⁵ Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
⁶ Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
⁷ Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Sint-Augustinus Cancer Center, Antwerp University Hospital, University of Antwerp, Antwerp 2610, Belgium.
⁹ Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁰ Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹¹ Department of Medicine/Dermatology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
¹² MD Anderson Cancer Center, Houston, TX 77030, USA.
¹³ Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address: sauvage@gene.com.

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.

MeSH terms

Anilides / chemistry
Anilides / therapeutic use*
Binding Sites
Carcinoma, Basal Cell / drug therapy
Carcinoma, Basal Cell / genetics*
DNA Copy Number Variations
DNA Mutational Analysis
Drug Resistance, Neoplasm / genetics*
Exome
Hedgehog Proteins / genetics
Humans
Kruppel-Like Transcription Factors / genetics
Models, Molecular
Mutation
Nuclear Proteins / genetics
Patched Receptors
Protein Structure, Tertiary
Pyridines / chemistry
Pyridines / therapeutic use*
Receptors, Cell Surface / genetics
Receptors, G-Protein-Coupled / chemistry
Receptors, G-Protein-Coupled / genetics*
Repressor Proteins / genetics
Sequence Analysis, DNA
Skin Neoplasms / drug therapy
Skin Neoplasms / genetics*
Smoothened Receptor
Zinc Finger Protein Gli2

Substances

Anilides
GLI2 protein, human
Hedgehog Proteins
HhAntag691
Kruppel-Like Transcription Factors
Nuclear Proteins
Patched Receptors
Pyridines
Receptors, Cell Surface
Receptors, G-Protein-Coupled
Repressor Proteins
SMO protein, human
SUFU protein, human
Smoothened Receptor
Zinc Finger Protein Gli2

Abstract

MeSH terms

Substances

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