Abstract C55: Nedd8-activating enzyme inhibitor pevonedistat synergizes with cisplatin and carboplatin through interference with nucleotide excision repair and interstrand cross-link repair mechanisms in non-small cell lung cancer

Abstract

Platinum-based therapies, both cisplatin and carboplatin, are utilized as part of first-line standard of care regimens for advanced non-small cell lung cancer (NSCLC), but overall response rate and overall survival remain limited, with a 5-year survival rate of 18%. Therefore, agents that can improve responses and survival are needed. Pevonedistat (MLN4924) is an investigational small molecule inhibitor of the Nedd8-activating enzyme (NAE) currently in Phase Ib clinical trials. Nedd8 is a small ubiquitin-like protein whose activation of the cullin family of E3 ubiquitin ligases is dependent on NAE activity. Importantly, pevonedistat synergized with carboplatin in a cell viability assay for 6 of 20 NSCLC cell lines tested in vitro, and synergy was also detected in the triple combination of carboplatin, pevonedistat, and paclitaxel. Order of addition experiments in the A549 NSCLC cell line demonstrated a benefit of simultaneous treatment or addition of pevonedistat prior to platinum treatment, while a reduced combination benefit was observed when cisplatin was added 24-48 hrs before pevonedistat. Levels of NAE pathway inhibition were similar in pevonedistat and pevonedistat+cisplatin treated cells, indicating that a drug-drug interaction was not likely the cause of the synergy. Using patient-derived xenograft (PDX) models a combination benefit of carboplatin and pevonedistat was demonstrated in a carboplatin-insensitive model but a similar improvement in response was not observed in a carboplatin-sensitive model, adding to evidence that pevonedistat might target platinum resistance mechanisms. To evaluate the mechanism of synergy between pevonedistat and platinum, in vitro experiments with RNAi were performed in 4 cell lines. These studies identified 2 mechanisms of synergy between pevonedistat and platinums in vitro. Depletion of genes within the TC-NER (transcription-coupled nucleotide excision repair) and ICR (interstrand crosslink repair) pathways reduced the synergy between pevonedistat and platinum, with the contribution of each pathway varying by cell line. Because these pathways are also implicated in the response to single agent platinums, the results suggest pevonedistat could delay completion of platinum-induced DNA repair and therefore result in enhanced cell death. Inhibition of neddylation of the E3 ubiquitin ligase CUL4-RBX1-DDB1-ERCC8 by pevonedistat may delay the TC-NER pathway, providing a direct mechanism of resistance reversal by pevonedistat. The combination of pevonedistat with carboplatin and paclitaxel is under evaluation as part of a phase 1b trial in adult patients with solid tumors (NCT01862328). Citation Format: David C. Bouck, Khristofer Garcia, Jonathan L. Blank, Xiaozhen J. Liu, Hugues Bernard, Allison J. Berger, Mike Kuranda, Erik Koenig, Eric S. Lightcap. Nedd8-activating enzyme inhibitor pevonedistat synergizes with cisplatin and carboplatin through interference with nucleotide excision repair and interstrand cross-link repair mechanisms in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C55.

Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors

“…These two patients discontinued carboplatin plus paclitaxel chemotherapy at cycle 9 and 13, respectively, and went on to maintenance therapy with single-agent pevonedistat; both patients are currently continuing treatment in cycle 43 without evidence of disease. Consistent with preclinical studies reporting synergy between pevonedistat and standard-of-care chemotherapy [13, 24], the long treatment durations in this study and objective responses in patients resistant to prior platinum/taxane therapy suggest the potential reversal of resistance by the addition of pevonedistat. Further exploration of pevonedistat and carboplatin plus paclitaxel in the platinum- and/or taxane-resistant setting is warranted.…”

“…Pevonedistat was shown in model systems to synergize with platinum-containing agents by interfering with NER and ICR pathways [13]. Previous studies reported that low ERCC1 expression is associated with clinical benefit in advanced cancer patients receiving platinum-based chemotherapy [19–21].…”

“…Pevonedistat has shown single-agent activity in various human solid tumor cell lines and xenograft models, as well as in patients with advanced solid tumors and hematologic malignancies [2, 4–12]. Pevonedistat delays completion of platinum-induced DNA repair in a transcription-coupled nucleotide excision repair (NER) and interstrand crosslink repair (ICR) pathway−dependent mechanism [13]. Excision repair cross-complementation group 1 (ERCC1), a component of the NER pathway, is thought to be involved in resistance to platinum-based therapies [14, 15] and predictive of decreased efficacy of platinum therapy [16–21].…”

“…Excision repair cross-complementation group 1 (ERCC1), a component of the NER pathway, is thought to be involved in resistance to platinum-based therapies [14, 15] and predictive of decreased efficacy of platinum therapy [16–21]. Pevonedistat enhances the antitumor activity of taxanes and gemcitabine, is synergistic with platinum salts, and is active in platinum-resistant tumors [13, 22–24].…”