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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.
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Details
1 Columbia University, Department of Biological Sciences, New York City, USA (GRID:grid.21729.3f) (ISNI:0000000419368729)
2 Columbia University, Department of Biological Sciences, New York City, USA (GRID:grid.21729.3f) (ISNI:0000000419368729); Harvard Medical School, Chemical Biology and Therapeutic Sciences Program, Broad Institute, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
3 Columbia University, Department of Systems Biology, New York City, USA (GRID:grid.21729.3f) (ISNI:0000000419368729)
4 Columbia University, Department of Biological Sciences, New York City, USA (GRID:grid.21729.3f) (ISNI:0000000419368729); Harvard Medical School, Laboratory of Systems Pharmacology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
5 Columbia University, Department of Biological Sciences, New York City, USA (GRID:grid.21729.3f) (ISNI:0000000419368729); Columbia University, Department of Chemistry, New York City, USA (GRID:grid.21729.3f) (ISNI:0000000419368729)