Targeting C4-Demethylating Genes in the Cholesterol Pathway Sensitizes Cancer Cells to EGF Receptor Inhibitors via Increased EGF Receptor Degradation

被引:57
作者
Sukhanova, Anna [1 ]
Gorin, Andrey [1 ]
Serebriiskii, Ilya G. [1 ]
Gabitova, Linara [1 ]
Zheng, Hui [1 ]
Restifo, Diana [1 ]
Egleston, Brian L. [2 ]
Cunningham, David [3 ,4 ]
Bagnyukova, Tetyana [1 ]
Liu, Hanqing [1 ]
Nikonova, Anna [1 ]
Adams, Gregory P. [1 ]
Zhou, Yan [2 ]
Yang, Dong-Hua [1 ]
Mehra, Ranee [1 ]
Burtness, Barbara [1 ]
Cai, Kathy Q. [1 ]
Klein-Szanto, Andres [1 ]
Kratz, Lisa E. [5 ]
Kelley, Richard I. [5 ]
Weiner, Louis M. [6 ]
Herman, Gail E. [3 ,4 ]
Golemis, Erica A. [1 ]
Astsaturov, Igor [1 ]
机构
[1] Fox Chase Canc Ctr, Dev Therapeut Program, Philadelphia, PA 19111 USA
[2] Fox Chase Canc Ctr, Biostat & Bioinformat Facil, Philadelphia, PA 19111 USA
[3] Ohio State Univ, Res Inst, Nationwide Childrens Hosp, Columbus, OH 43210 USA
[4] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA
[5] Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD USA
[6] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA
关键词
EPIDERMAL-GROWTH-FACTOR; DIFFERENTIAL REGULATION; STEROL; MOUSE; CETUXIMAB; MEIOSIS; NSDHL; HEAD; INTERNALIZATION; AMPLIFICATION;
D O I
10.1158/2159-8290.CD-12-0031
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:96 / 111
页数:16
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