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Sukhanova A , Gorin A , Serebriiskii IG , Gabitova L , Zheng H , Restifo D , Egleston BL , Cunningham D , Bagnyukova T , Liu H , Nikonova A , Adams GP , Zhou Y , Yang DH , Mehra R , Burtness B , Cai KQ , Klein-Szanto A , Kratz LE , Kelley RI , Weiner LM , Herman GE , Golemis EA , Astsaturov I
Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation
Cancer Discov. 2013 Jan;3(1) :96-111
PMID: 23125191    PMCID: PMC3546138   
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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. SIGNIFICANCE: 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.
Notes
Sukhanova, Anna Gorin, Andrey Serebriiskii, Ilya G Gabitova, Linara Zheng, Hui Restifo, Diana Egleston, Brian L Cunningham, David Bagnyukova, Tetyana Liu, Hanqing Nikonova, Anna Adams, Gregory P Zhou, Yan Yang, Dong-Hua Mehra, Ranee Burtness, Barbara Cai, Kathy Q Klein-Szanto, Andres Kratz, Lisa E Kelley, Richard I Weiner, Louis M Herman, Gail E Golemis, Erica A Astsaturov, Igor CA-06927/CA/NCI NIH HHS/United States K22 CA160725/CA/NCI NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States R01 CA-63366/CA/NCI NIH HHS/United States R01 CA050633/CA/NCI NIH HHS/United States R01 CA063366/CA/NCI NIH HHS/United States R01 CA113342/CA/NCI NIH HHS/United States R01 CA50633/CA/NCI NIH HHS/United States R01 HD38572/HD/NICHD NIH HHS/United States R21 CA164205/CA/NCI NIH HHS/United States U54 CA149147/CA/NCI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Cancer discovery Nihms418921 Cancer Discov. 2013 Jan;3(1):96-111. doi: 10.1158/2159-8290.CD-12-0031. Epub 2012 Nov 2.