@article {686015,
	title = {Mesenchymal subtype neuroblastomas are addicted to TGF-βR2/HMGCR-driven protein geranylgeranylation},
	journal = {Sci Rep},
	volume = {10},
	number = {1},
	year = {2020},
	month = {2020 07 01},
	pages = {10748},
	abstract = {The identification of targeted agents with high therapeutic index is a major challenge for cancer drug discovery. We found that screening chemical libraries across neuroblastoma (NBL) tumor subtypes for selectively-lethal compounds revealed metabolic dependencies that defined each subtype. Bioactive compounds were screened across cell models of mesenchymal (MESN) and MYCN-amplified (MYCNA) NBL subtypes, which revealed the mevalonate and folate biosynthetic pathways as MESN-selective dependencies. Treatment with lovastatin, a mevalonate biosynthesis inhibitor, selectively inhibited protein prenylation and induced apoptosis in MESN cells, while having little effect in MYCNA lines. Statin sensitivity was driven by HMGCR expression, the rate-limiting enzyme for cholesterol synthesis, which correlated with statin sensitivity across NBL cell lines, thus providing a drug sensitivity biomarker. Comparing expression profiles from sensitive and resistant cell lines revealed a TGFBR2 signaling axis that regulates HMGCR, defining an actionable addiction in that leads to MESN-subtype-dependent apoptotic cell death.},
	keywords = {Antineoplastic Agents, Apoptosis, Biomarkers, Tumor, Cell Line, Tumor, Fluvastatin, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Lovastatin, Methotrexate, N-Myc Proto-Oncogene Protein, Neuroblastoma, Protein Prenylation, Receptor, Transforming Growth Factor-beta Type II, RNA, Small Interfering, Signal Transduction, Triamterene},
	issn = {2045-2322},
	doi = {10.1038/s41598-020-67310-0},
	author = {Stokes, Michael E and Small, Jonnell Candice and Vasciaveo, Alessandro and Shimada, Kenichi and Hirschhorn, Tal and Califano, Andrea and Stockwell, Brent R.}
}
