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Clin Cancer Res. 2019 Jun 1;25(11):3430-3442. doi: 10.1158/1078-0432.CCR-18-0440. Epub 2019 Feb 12.

Combined Aurora Kinase A (AURKA) and WEE1 Inhibition Demonstrates Synergistic Antitumor Effect in Squamous Cell Carcinoma of the Head and Neck.

Author information

1
Section of Medical Oncology, Department of Internal Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
2
Biosample Repository, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
3
Department of Biostatistics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
4
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
5
Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut.
6
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
7
Section of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
8
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
9
Section of Medical Oncology, Department of Internal Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. barbara.burtness@yale.edu.

Abstract

PURPOSE:

Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC) commonly bear disruptive mutations in TP53, resulting in treatment resistance. In these patients, direct targeting of p53 has not been successful, but synthetic lethal approaches have promise. Although Aurora A kinase (AURKA) is overexpressed and an oncogenic driver, its inhibition has only modest clinical effects in HPV-negative HNSCC. We explored a novel combination of AURKA and WEE1 inhibition to overcome intrinsic resistance to AURKA inhibition.Experimental Design: AURKA protein expression was determined by fluorescence-based automated quantitative analysis of patient specimens and correlated with survival. We evaluated treatment with the AURKA inhibitor alisertib (MLN8237) and the WEE1 inhibitor adavosertib (AZD1775), alone or in combination, using in vitro and in vivo HNSCC models.

RESULTS:

Elevated nuclear AURKA correlated with worse survival among patients with p16(-) HNSCC. Alisertib caused spindle defects, G2-M arrest and inhibitory CDK1 phosphorylation, and cytostasis in TP53 mutant HNSCC FaDu and UNC7 cells. Addition of adavosertib to alisertib instead triggered mitotic entry and mitotic catastrophe. Moreover, in FaDu and Detroit 562 xenografts, this combination demonstrated synergistic effects on tumor growth and extended overall survival compared with either vehicle or single-agent treatment.

CONCLUSIONS:

Combinatorial treatment with adavosertib and alisertib leads to synergistic antitumor effects in in vitro and in vivo HNSCC models. These findings suggest a novel rational combination, providing a promising therapeutic avenue for TP53-mutated cancers.

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