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.
Highlights
The identification of targeted agents with high therapeutic index is a major challenge for cancer drug discovery
No correlation was observed between transforming growth factor beta receptor 2 (TGFBR2) and ZEB1 across tumors (Fig. 4H; Supplemental Figure S5D,E), suggesting that TGFBR2-ZEB2 signaling is preferentially active in the MESN NBL subtype
By screening for subtype-selective molecules, tractable metabolic dependencies were revealed that underpin the MESN NBL subtype
Summary
Can block prenylation of specific GTPases (Fig. 2A); FTI-277 is a selective FT inhibitor while GGTI-298 is a cell permeable selective GGTase[1] inhibitor (Supplemental Figure S3A–C)[13,27]. Suppression of HMGCRconferred sensitivity to the MYCNA cell line, and induced further hypersensitivity in MESN cells, supporting the relationship between HMGCRexpression and statin sensitivity in neuroblastoma[30,31] (Fig. 3E) These findings were validated across statin compounds by confirming similar results with atorvastatin and cerivastatin (Supplemental Figure S4B,C). Comparing MYCNA and MESN profiles revealed that, similar to cell lines, both TGFBR2 and REST expression were elevated in MESN tumors and tightly correlated across samples, as determined by linear regression analysis (r2 = 0.5523; p < 0.0001; Fig. 4E; Supplemental Figure S5A,B). To test whether a similar mechanism may drive sensitivity in MESN NBL, the relationship between TGFBR2 expression and transcripts of two EMT effectors, ZEB1 and ZEB2, was compared across tumor profiles by linear regression analysis. No correlation was observed between TGFBR2 and ZEB1 across tumors (Fig. 4H; Supplemental Figure S5D,E), suggesting that TGFBR2-ZEB2 signaling is preferentially active in the MESN NBL subtype
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