Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation.

Abstract

UNLABELLED:

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.

• Authors: Anna Sukhanova, Andrey Gorin, Ilya G Serebriiskii, Linara Gabitova, Hui Zheng, Diana Restifo, Brian L Egleston, David Cunningham, Tetyana Bagnyukova, Hanqing Liu, Anna Nikonova, Gregory P Adams, Yan Zhou, Dong-Hua Yang, Ranee Mehra, Barbara Burtness, Kathy Q Cai, Andres Klein-Szanto, Lisa E Kratz, Richard I Kelley, Louis M Weiner, Gail E Herman, Erica A Golemis, Igor Astsaturov
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 1 Pg. 96-111 (Jan 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23125191 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Cholesterol
• Mixed Function Oxygenases
• 3-Hydroxysteroid Dehydrogenases
• Nsdhl protein, mouse
• methylsterol monooxygenase
• ErbB Receptors
• Cetuximab

Topics

• 3-Hydroxysteroid Dehydrogenases (genetics, metabolism)
• Animals
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Cell Line, Tumor
• Cetuximab
• Cholesterol (metabolism)
• Endocytosis
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Male
• Mice
• Mice, SCID
• Mice, Transgenic
• Mixed Function Oxygenases (genetics)
• Neoplasms (drug therapy, genetics, metabolism)
• Protein Transport