Combined Aurora Kinase A (AURKA) and WEE1 Inhibition Demonstrates Synergistic Antitumor Effect in Squamous Cell Carcinoma of the Head and Neck
Combined Aurora Kinase A (AURKA) and WEE1 Inhibition Demonstrates Synergistic Antitumor Effect in Squamous Cell Carcinoma of the Head and Neck
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DOI：
10.1158/1078-0432.ccr-18-0440
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发表时间：
2019-06-01
影响因子：
11.5
通讯作者：
Burtness, Barbara
中科院分区：
文献类型：
--
作者：
Lee, Jong Woo;Parameswaran, Janaki;Burtness, Barbara
目的：人乳头瘤病毒（HPV）阴性的头颈部鳞状细胞癌（HNSCC）通常在TP 53中携带破坏性突变，导致治疗耐药性。在这些患者中，直接靶向p53尚未成功，但合成致死方法有希望。尽管极光A激酶（AURKA）过表达并且是致癌驱动因子，但其抑制在HPV阴性HNSCC中仅具有适度的临床作用。我们探索了一种新的组合AURKA和WEE 1抑制，以克服内在的阻力AURKA inhibition.Experimental Design：AURKA蛋白的表达测定基于荧光的自动定量分析患者标本和生存相关。我们评估了AURKA抑制剂alisertib（MLN 8237）和WEE 1抑制剂adavosertib（AZD 1775）单独或联合使用的治疗，使用体外和体内HNSCCmodel.Results：核AURKA升高与p16（-）HNSCC患者的生存率较差相关。Alisertib在TP 53突变型HNSCC FaDu和UNC 7细胞中引起纺锤体缺陷、G（2）-M阻滞和抑制性CDK 1磷酸化以及细胞停滞。在阿立塞替中添加adavosertib反而引发有丝分裂进入和有丝分裂灾难。此外，在FaDu和底特律562异种移植瘤，这种组合表现出协同效应的肿瘤生长和延长的总生存期相比，无论是车辆或单剂treatment.Conclusions：联合治疗与adavosertib和alisertib导致协同抗肿瘤作用在体外和体内HNSCC模型。这些发现表明了一种新的合理组合，为TP 53突变的癌症提供了一种有希望的治疗途径。
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, G(2)-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.