The nearly ubiquitous development of chemoresistant disease remains a major obstacle against improving outcomes for patients with
ovarian cancer. In this investigation, we evaluated the preclinical activity of
MLN4924, an investigational inhibitor of the NEDD8-activating
enzyme, in
ovarian cancer cells. Efficacy of
MLN4924 both alone and in combination with
platinum was assessed. Overall, single-agent
MLN4924 exhibited moderate activity in
ovarian cancer cell lines. However, the combination of
MLN4924 with
cisplatin or
carboplatin produced synergistic effects in SKOV3 and ES2 cells, as well as in primary
ovarian cancer cell lines established from high-grade serous, clear cell, and serous borderline ovarian
tumors. The efficacy of
cisplatin plus
MLN4924 was also evident in several in vitro models of
platinum-resistant
ovarian cancer. Mechanistically, the combination of
cisplatin and
MLN4924 was not associated with
DNA re-replication, altered
platinum-
DNA adduct formation, abrogation of FANCD2 monoubiquitination, or CHK1 phosphorylation. An
siRNA screen was used to investigate the contribution of each member of the
cullin RING
ligase (CRL) family of E3
ubiquitin ligases, the best-characterized downstream mediators of
MLN4924's
biologic effects.
Cisplatin-induced cytotoxicity was augmented by depletion of CUL3, and antagonized by siCUL1 in both ES2 and SKOV3
ovarian cancer cells. This investigation identifies inhibition of neddylation as a novel mechanism for overcoming
platinum resistance in vitro, and provides a strong rationale for clinical investigations of
platinum and
MLN4924 combinations in
ovarian cancer.