Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR

Abstract

Summary Meiosis activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by EGFR or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRASG12D. Strikingly, Nsdhl inactivation antagonized the growth of skin tumors, while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, while an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites can be an effective strategy against carcinomas with activated EGFR-KRAS signaling.

An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers

“…We focused on cholesterol homeostasis because: 1) GBM cells are highly dependent on cholesterol for survival (Bovenga et al, 2015); 2) EGFR mutations can regulate cholesterol homeostasis in GBM and possibly in other types of cancers (Gabitova et al, 2015; Guo et al, 2011); 3) the brain has a unique mechanism of cholesterol regulation that may expose a targetable vulnerability specific to tumor cells in this organ (Dietschy and Turley, 2001); and 4) anecdotal evidence from a Phase 1 clinical trial raised the possibility that a highly brain penetrant compound, LXR-623, could be used to exploit this vulnerability (Katz et al, 2009). …”

“…A strong case has been made for nuclear hormone receptor modulators as potential cancer drugs (Gronemeyer et al, 2004), including LXR modulators that show activity against melanoma, intestinal cancers, squamous cell cancers, prostate cancers cells and breast cancer cell lines (Flaveny et al, 2015; Gabitova et al, 2015; Lin and Gustafsson, 2015; Lo Sasso et al, 2013; Nguyen-Vu et al, 2013; Pencheva et al, 2014; Pommier et al, 2013). However, what is unanticipated and important from our studies is the critical role that tissue type and organ context seems to play in determining the activity of a specific LXR modulator.…”

EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer

“…27), PTEN (1:100, 9559, Cell Signaling Technology), NSDHL (1:100, 15111-1-AP, Proteintech Group; refs. 20, 21), and BCAR1 (1:250, ab31831, Abcam). Primary antibodies were visualized using a Cy-5-tyramide signal amplification system (TSA; AT705A, PerkinElmer).…”

“…These include not only additional EGFR family members, such as HER2 (16), but also components of EGFR/HER2 effector cascades that influence survival: PTEN, PI3K, AKT, and BCAR1 (16–18), and proteins that regulate EGFR/HER2 activity, trafficking, and expression, such as CBL, GRB2, and NSDHL (19, 20). Among these, NSDHL (NADP-dependent steroid dehydrogenase–like enzymes), required for the conversion of squalene to cholesterol (21), has recently been shown to have noncanonical function as a regulator of EGFR recycling (19, 20). Depletion or genetic loss of NSDHL significantly disrupts EGFR signaling by reducing total levels of EGFR (22).…”

ATP‑binding cassette transporter A1: A promising therapy target for prostate cancer (Review)

“…Of note, the epidermal growth factor receptor (EGFR) signal opposes the effects of LXRα on cholesterol homeostasis, whereas EGFR inhibitors interact with LXRα agonists to destroy cancer cells. Inhibition of activation of LXRα by sterol metabolites may be an effective strategy for targeting EGFR-KRAS signaling against cancer (42).…”