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

Neoplasia : an International Journal for Oncology Research
Joanna S YiW Clay Gustafson

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 profou...Continue Reading

References

Jun 23, 1999·Oncogene·C E NesbitE V Prochownik
Nov 3, 2007·Cancer Research·Chengyuan XueAndrei V Gudkov
Feb 11, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jane Carr-WilkinsonDeborah A Tweddle
Feb 19, 2010·Nature·Rameen BeroukhimMatthew Meyerson
Jul 8, 2010·Cancer Chemotherapy and Pharmacology·E Claire DeesHoward Burris
Jul 24, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Olena MorozovaMarco A Marra
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Oct 22, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Mark G ManfrediTodd B Sells
Mar 1, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Daruka MahadevanWenqing Qi
Apr 11, 2012·International Journal of Cancer. Journal International Du Cancer·Kevin R KellyJennifer S Carew
Jul 4, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Andres CervantesJosep Tabernero
Sep 19, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Yael P MosséSusan M Blaney
Oct 2, 2012·Cell·Charles Y LinRichard A Young
Feb 23, 2013·Cancer Discovery·Alexandre PuissantKimberly Stegmaier
Dec 4, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Pratiti BandopadhayayYoon-Jae Cho
Jan 29, 2014·Proceedings of the National Academy of Sciences of the United States of America·Lesley A Mathews GrinerCraig J Thomas
Sep 2, 2014·Cancer Cell·William Clay GustafsonWilliam A Weiss
Oct 1, 2014·PloS One·Martin MichaelisJindrich Cinatl
Jun 30, 2015·Nature Genetics·Thomas F EleveldJohn M Maris
Aug 26, 2017·Annals of Oncology : Official Journal of the European Society for Medical Oncology·D B DoroshowP M LoRusso
Sep 26, 2017·Drug Discovery Today·Mahalakshmi Ramadoss, Vijayalakshmi Mahadevan
Mar 8, 2018·Oncogene·Sara BolinFredrik J Swartling
Aug 11, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Steven G DuBoisAraz Marachelian
Aug 29, 2018·Neoplasia : an International Journal for Oncology Research·Joshua FelgenhauerNilay Shah
Dec 14, 2018·Science·Sandra AckermannMatthias Fischer
Feb 20, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Yael P MosséBrenda J Weigel

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