2. Academic Validation
  3. The synergy of BET inhibitors with aurora A kinase inhibitors in MYCN-amplified neuroblastoma is heightened with functional TP53

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

  • Neoplasia. 2021 Jun;23(6):624-633. doi: 10.1016/j.neo.2021.05.003.
Joanna S Yi 1,  Oscar Sias-Garcia 2,  Nicole Nasholm 3,  Xiaoyu Hu 2,  Amanda Balboni Iniguez 4,  Matthew D Hall 5,  Mindy Davis 5,  Rajarshi Guha 5,  Myrthala Moreno-Smith 2,  Eveline Barbieri 2,  Kevin Duong 2,  Jessica Koach 6,  Jun Qi 7,  James E Bradner 7,  Kimberly Stegmaier 4,  William A Weiss 6,  W Clay Gustafson 8
Affiliations

Affiliations

  • 1 Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts, USA. Electronic address: Joanna.yi@bcm.edu.
  • 2 Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, Texas, USA.
  • 3 Department of Pediatrics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA.
  • 4 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts, USA; Broad Institute, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
  • 5 National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
  • 6 Department of Pediatrics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA; Department of Neurology and Neurological Surgery, University of California, San Francisco, California, USA.
  • 7 Broad Institute, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 8 Department of Pediatrics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA. Electronic address: Clay.Gustafson@ucsf.edu.
PMID: 34107377 DOI: 10.1016/j.neo.2021.05.003
Abstract

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 ∼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.

Keywords

Apoptosis; MYCN; Neuroblastoma; Synergy; TP53.

Figures
Products