Abstract
AbstractRB1 loss (RB1null) or MYCN amplification (MYCNamp) in fetal human retina causes retinoblastoma. SKP2 loss kills RB1null cells, but small molecule SKP2 inhibitors remain unexplored therapeutically. Whether SKP2 is synthetic lethal in MYCNamp retinoblastoma is unclear. SKP2 is the substrate recognition component of two Cullin-RING Ligase complexes (CRL1SKP2/SCFSKP2, and CRL4SKP2), a family of multiprotein E3 ubiquitin ligases. NEDD8 activating enzyme (NAE) is required for Cullin neddylation and thus CRL activation. Here, we show that the NAE inhibitor, Pevonedistat (MLN4924), potently inhibits RB1null and MYCNamp tumors. Intravitreal MLN4924 suppressed multiple human xenografts with EC80s from 20 ng to 3.5 μg. Maximum tolerated dose (MTD) was 10–30 μg, highlighting a favorable therapeutic window. Inhibition of Cullin neddylation was similar in all cases, but cellular effects ranged from G1 arrest with apoptosis to G2/M arrest with endoreplication. However, even in less sensitive lines (EC50 ≈ 1 μM), prolonged exposure was lethal or induced persistent cytostasis. Mechanistically, depleting any single Cullin did not fully recapitulate drug phenotypes, but sensitivity to SKP2 loss correlated with that of drug. Thus, intravitreal MLN4924 is a promising new retinoblastoma therapy, mimicking the cancer-specific lethality of eliminating SKP2 complexes.
Funder
Gouvernement du Canada | Canadian Institutes of Health Research
Krembil Foundation
Cancer Research Society
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Cited by
38 articles.
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