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 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.
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Hayley J
authors.initials: HJ
authors.lastname: Sharpe
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Gregoire
authors.initials: G
authors.lastname: Pau
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Gerrit J
authors.initials: GJ
authors.lastname: Dijkgraaf
authors.affiliation: Paris 7 Hôpital Saint-Louis, Paris 75010, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Basset-Seguin
authors.affiliation: Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Januario
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Vickie
authors.initials: V
authors.lastname: Tsui
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Alison B
authors.initials: AB
authors.lastname: Durham
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bourgon
authors.affiliation: Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
authors.affiliation: Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kavita Y
authors.initials: KY
authors.lastname: Sarin
authors.affiliation: Sint-Augustinus Cancer Center, Antwerp University Hospital, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Fisher
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Department of Medicine/Dermatology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Sofen
authors.affiliation: MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Migden
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080, USA. Electronic address: sauvage@gene.com.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000627:therapeutic use*; D001665:Binding Sites; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000235:genetics*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059472:Exome; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000072079:Patched Receptors; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics*; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2
chemical_list: D000813:Anilides; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000072079:Patched Receptors; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; C491023:SMO protein, human; C490764:SUFU protein, human; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2