title: Smoothened variants explain the majority of drug resistance in basal cell carcinoma.
abstract: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Scott X
authors.initials: SX
authors.lastname: Atwood
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kavita Y
authors.initials: KY
authors.lastname: Sarin
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ramon J
authors.initials: RJ
authors.lastname: Whitson
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jiang R
authors.initials: JR
authors.lastname: Li
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Geurim
authors.initials: G
authors.lastname: Kim
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Melika
authors.initials: M
authors.lastname: Rezaee
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mina S
authors.initials: MS
authors.lastname: Ally
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jinah
authors.initials: J
authors.lastname: Kim
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Yao
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Anne Lynn S
authors.initials: AL
authors.lastname: Chang
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: oro@stanford.edu.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Oro
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: tangy@stanford.edu.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000627:therapeutic use*; D001665:Binding Sites; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059472:Exome; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000072086:Smoothened Receptor
chemical_list: D000813:Anilides; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor