Tanaka Noriaki, Patel Ameeta A, Wang Jiping, Frederick Mitchell J, Kalu Nene N, Zhao Mei, Fitzgerald Alison L, Xie Tong-xin, Silver Natalie L, Caulin Carlos, Zhou Ge, Skinner Heath D, Johnson Faye M, Myers Jeffrey N, Osman Abdullah A
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2015 Nov 1;21(21):4831-44. doi: 10.1158/1078-0432.CCR-15-0279. Epub 2015 Jun 29.
Although the majority of patients with HPV(+) oropharyngeal cancers have a favorable prognosis, there are some patients with tumors that are resistant to aggressive chemoradiotherapy with unusual patterns of locoregional and systemic recurrences. Therefore, more effective therapies are needed. In this study, we investigated the chemosensitizing efficacy of the selective Wee-1 kinase inhibitor, AZD-1775, in HPV(+) head and neck squamous cell carcinoma (HNSCC).
Clonogenic survival assays and an orthotopic mouse model of HPV(+) oral cancer were used to examine the in vitro and in vivo sensitivity of HPV(+) HNSCC cell lines to AZD-1775 in combination with cisplatin, respectively. Cell-cycle analysis, DNA damage (γH2AX), homologous recombination (HR), and apoptosis were examined to dissect molecular mechanisms.
We found that AZD-1775 displays single-agent activity and enhances the response of HPV(+) HNSCC cells to cisplatin both in vitro and in vivo. The sensitivity of the HPV(+) HNSCC cells to AZD-1775 alone or in combination with cisplatin was associated with G2 checkpoint abrogation, persistent DNA damage, and apoptosis induction. This finding of AZD-1775 increasing the sensitivity of HPV(+) HNSCC cells to cisplatin through apoptosis was not seen previously in the HPV(-) HNSCC cancer cells and is accompanied by a decreased expression of the antiapoptotic proteins, MCl-1and XIAP, which appear to be cleaved following AZD-1775 treatment.
AZD-1775 selectively sensitizes HPV(+) HNSCC cells and orthotopic oral xenografts to cisplatin through apoptosis and support the clinical investigation of AZD-1775 in combination with cisplatin particularly in patients with advanced and recurrent metastatic HPV(+) HNSCC tumors.
尽管大多数人乳头瘤病毒（HPV）阳性口咽癌患者预后良好，但仍有一些患者的肿瘤对积极的放化疗耐药，出现局部区域和全身复发的异常模式。因此，需要更有效的治疗方法。在本研究中，我们研究了选择性Wee-1激酶抑制剂AZD-1775对HPV阳性头颈部鳞状细胞癌（HNSCC）的化疗增敏效果。
分别使用克隆形成存活试验和HPV阳性口腔癌原位小鼠模型，检测HPV阳性HNSCC细胞系对AZD-1775联合顺铂的体外和体内敏感性。通过细胞周期分析、DNA损伤（γH2AX）、同源重组（HR）和细胞凋亡检测来剖析分子机制。
我们发现AZD-1775具有单药活性，并且在体外和体内均增强了HPV阳性HNSCC细胞对顺铂的反应。HPV阳性HNSCC细胞对单独使用AZD-1775或联合顺铂的敏感性与G2检查点废除、持续性DNA损伤和细胞凋亡诱导有关。AZD-1775通过细胞凋亡增加HPV阳性HNSCC细胞对顺铂敏感性这一发现，在HPV阴性HNSCC癌细胞中未见报道，并且伴随着抗凋亡蛋白MCl-1和XIAP表达降低，这两种蛋白在AZD-1775处理后似乎被切割。
AZD-1775通过细胞凋亡使HPV阳性HNSCC细胞和原位口腔异种移植物对顺铂敏感，并支持AZD-1775联合顺铂的临床研究，特别是在晚期和复发性转移性HPV阳性HNSCC肿瘤患者中。
