Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy

Arthur Aubry; Tao Yu; Rod Bremner

doi:10.1038/s41420-020-0237-8

Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy

Cell Death Discov. 2020 Jan 20:6:2. doi: 10.1038/s41420-020-0237-8. eCollection 2020.

Authors

Arthur Aubry^{1

2}, Tao Yu¹, Rod Bremner^{1

2

3}

Affiliations

¹ 1Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, 600 University Avenue, Toronto, ON M5G 1X5 Canada.
² 2Department of Laboratory Medicine and Pathobiology, University of Toronto, 27 King's College Circle, Toronto, ON M5S 1A1 Canada.
³ 3Department of Ophthalmology and Vision Science, University of Toronto, 27 King's College Circle, Toronto, ON M5S 1A1 Canada.

Abstract

RB1 loss (RB1 ^null ) or MYCN amplification (MYCN ^amp ) in fetal human retina causes retinoblastoma. SKP2 loss kills RB1 ^null cells, but small molecule SKP2 inhibitors remain unexplored therapeutically. Whether SKP2 is synthetic lethal in MYCN ^amp retinoblastoma is unclear. SKP2 is the substrate recognition component of two Cullin-RING Ligase complexes (CRL1^SKP2/SCF^SKP2, and CRL4^SKP2), 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 RB1 ^null and MYCN ^amp 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.

Keywords: Eye cancer; Targeted therapies.