title: Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation.
abstract: Persistent signaling by the oncogenic EGF receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of 2 sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase-like) and its partner, NSDHL (NADP-dependent steroid dehydrogenase-like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody. Analysis of Nsdhl-deficient Bpa(1H/+) mice confirmed dramatic and selective loss of internalized platelet-derived growth factor receptor in fibroblasts, and reduced activation of EGFR and its effectors in regions of skin lacking NSDHL.
  
  
  CONCLUSIONS
  This work identifies a critical role for SC4MOL and NSDHL in the regulation of EGFR signaling and endocytic trafficking and suggests novel strategies to increase the potency of EGFR antagonists in tumors.
authors.affiliation: Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Sukhanova
authors.forename: Andrey
authors.initials: A
authors.lastname: Gorin
authors.forename: Ilya G
authors.initials: IG
authors.lastname: Serebriiskii
authors.forename: Linara
authors.initials: L
authors.lastname: Gabitova
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Diana
authors.initials: D
authors.lastname: Restifo
authors.forename: Brian L
authors.initials: BL
authors.lastname: Egleston
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Tetyana
authors.initials: T
authors.lastname: Bagnyukova
authors.forename: Hanqing
authors.initials: H
authors.lastname: Liu
authors.forename: Anna
authors.initials: A
authors.lastname: Nikonova
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Adams
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Yang
authors.forename: Ranee
authors.initials: R
authors.lastname: Mehra
authors.forename: Barbara
authors.initials: B
authors.lastname: Burtness
authors.forename: Kathy Q
authors.initials: KQ
authors.lastname: Cai
authors.forename: Andres
authors.initials: A
authors.lastname: Klein-Szanto
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Kratz
authors.forename: Richard I
authors.initials: RI
authors.lastname: Kelley
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiner
authors.forename: Gail E
authors.initials: GE
authors.lastname: Herman
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
authors.forename: Igor
authors.initials: I
authors.lastname: Astsaturov
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab; D002784:Cholesterol / Q000378:metabolism; D004705:Endocytosis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002784:Cholesterol; D006899:Mixed Function Oxygenases; D015096:3-Hydroxysteroid Dehydrogenases; C515670:Nsdhl protein, mouse; C027532:methylsterol monooxygenase; D066246:ErbB Receptors; D000068818:Cetuximab