☆ 4.3 Article

The synergy of BET inhibitors with aurora A kinase inhibitors in MYCN-amplified neuroblastoma is heightened with functional TP53

NEOPLASIA (2021)

Journal

NEOPLASIA

Volume 23, Issue 6, Pages 624-633

Publisher

ELSEVIER SCIENCE INC

DOI: 10.1016/j.neo.2021.05.003

Keywords

Neuroblastoma; MYCN; TP53; Synergy; Apoptosis

Funding

Hyundai Hope on Wheels Scholar Award
Alex's Lemonade Stand Centers of Excellence Developmental Therapeutics Scholar Award
NIH Texas Children's Cancer and Hematology Centers K12 Clinical Pharmacology Scholar Award
NIH [R01NS088355, P01CA217959, P30CA082103]
Alex's Lemonade Stand [K08NS079485]
DOD [W81XWH-15-1-0166]
Intramural Research Programs of the National Center for Advancing Translational Sciences, National Institutes of Health

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Abstract

Amplification of MYCN in neuroblastoma is associated with poor prognosis, and BET bromodomain inhibitors have been shown to indirectly target MYCN by downregulating its transcription. In this study, BET bromodomain inhibitors were found to synergize with aurora kinase A inhibitors in MYCN-amplified neuroblastoma cell lines, with the combination showing improved efficacy, particularly in the context of functional TP53. This combination therapy warrants further investigation in pediatric clinical trials.

Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease. We and others have shown BET bromodomain inhibitors (BETi) target MYCN indirectly by downregulating its transcription. Here we sought to identify agents that synergize with BETi and to identify biomarkers of resistance. We previously performed a viability screen of similar to 1,900 oncology-focused compounds combined with BET bromodomain inhibitors against MYCN-amplified NBL cell lines. Reanalysis of our screening results prominently identified inhibitors of aurora kinase A (AURKAi) to be highly synergistic with BETi. We confirmed the anti-proliferative effects of several BETi+AURKAi combinations in MYCN-amplified NBL cell lines. Compared to single agents, these combinations cooperated to decrease levels of N-myc. We treated both TP53-wild type and mutant, MYCN-amplified cell lines with the BETi JQ1 and the AURKAi Alisertib. The combination had improved efficacy in the TP53-WT context, notably driving apoptosis in both genetic backgrounds. JQ1+Alisertib combination treatment of a MYCN-amplified, TP53-null or TP53-restored genetically engineered mouse model of NBL prolonged survival better than either single agent. This was most profound with TP53 restored, with marked tumor shrinkage and apoptosis induction in response to combination JQ1+Alisertib. BETi+AURKAi in MYCN-amplified NBL, particularly in the context of functional TP53, provided anti-tumor benefits in preclinical models. This combination should be studied more closely in a pediatric clinical trial.

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Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma

Krista M. Dalton, Timothy L. Lochmann, Konstantinos Floros, Marissa L. Calbert, Richard Kurupi, Giovanna T. Stein, Joseph McClanaghan, Ellen Murchie, Regina K. Egan, Patricia Greninger, Mikhail Dozmorov, Sivapriya Ramamoorthy, Madhavi Puchalapalli, Bin Hu, Lisa Shock, Jennifer Koblinski, John Glod, Sosipatros A. Boikos, Cyril H. Benes, Anthony C. Faber

Summary: MYCN-amplified neuroblastoma is sensitive to the combination of the lactate transporter MCT1 inhibitor AZD3965 and the mitochondrial complex I inhibitor phenformin. Low expression of MCT4, combined with high expression of MCT2 and MCT1 chaperone CD147 in MYCN-amplified neuroblastoma, confers sensitivity to this combination therapy, leading to disruption of glycolysis and oxidative phosphorylation, ATP production, endoplasmic reticulum stress, and ultimately, cell death.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2021)