mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC.
mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC.
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DOI：
10.18632/oncotarget.8286
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Lee JH
中科院分区：
文献类型：
--
作者：
Coppock JD;Vermeer PD;Vermeer DW;Lee KM;Miskimins WK;Spanos WC;Lee JH
复发/转移性人乳头瘤病毒阳性(HPV+)头颈部鳞状细胞癌(HNSCC)的有效治疗方法有限。为了帮助治疗的发展，我们描述了一种新的HPV+HNSCC复发/转移的小鼠模型。对亲代肿瘤细胞系及其四个复发/转移衍生物的进一步分析导致了对这种否则致命的疾病的有效治疗选择的临床前测试。逆相蛋白质阵列确定了亲代和复发/转移细胞系中的关键信号级联。虽然复发/转移细胞系的蛋白表达谱不同，但与mTOR信号级联相关的激活蛋白是一个共同点。基于这些数据，mTOR抑制被评估为复发/转移性疾病的辅助治疗。体外用免疫印迹法、海马法、增殖试验、克隆形成试验和迁移试验评价mTOR活性和治疗反应。在体内比较标准护理顺铂/放射治疗(CRT)和CRT/雷帕霉素。在克隆形成实验中，小剂量雷帕霉素抑制mTOR信号转导，抑制细胞增殖(43%)和迁移(62%)，同时增强CRT诱导的细胞毒性(3.3倍)。此外，雷帕霉素使对CRT耐药的转移性肿瘤重新对体内治疗敏感，提高了长期治愈率(根据复发/转移细胞系的不同，0-30%提高到78%-100%)，并限制了淋巴转移(32%)和肺转移负担(30倍)。对免疫受损小鼠的研究表明，雷帕霉素对肿瘤转移的影响不依赖于适应性免疫反应。这些数据提示mTOR激活在HPV+HNSCC复发/转移疾病中的作用，辅助性mTOR抑制可能加强对原发部位耐药、转移细胞群的治疗，并限制远处转移。
Effective treatments for recurrent/metastatic human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) are limited. To aid treatment development, we characterized a novel murine model of recurrent/metastatic HPV+ HNSCC. Further analysis of the parental tumor cell line and its four recurrent/metastatic derivatives led to preclinical testing of an effective treatment option for this otherwise fatal disease. Reverse phase protein arrays identified key signaling cascades in the parental and recurrent/metastatic cell lines. While protein expression profiles differed among the recurrent/metastatic cell lines, activated proteins associated with the mTOR signaling cascade were a commonality. Based on these data, mTOR inhibition was evaluated as an adjuvant treatment for recurrent/metastatic disease. mTOR activity and treatment response were assessed in vitro by western blot, Seahorse, proliferation, clonogenic, and migration assays. Standard-of-care cisplatin/radiation therapy (CRT) versus CRT/rapamycin were compared in vivo. Low-dose rapamycin inhibited mTOR signaling, decreasing proliferation (43%) and migration (62%) while it enhanced CRT-induced cytotoxicity (3.3 fold) in clonogenic assays. Furthermore, rapamycin re-sensitized CRT-resistant, metastatic tumors to treatment in vivo, improving long-term cures (0–30% improved to 78–100%, depending on the recurrent/metastatic cell line) and limiting lymph node metastasis (32%) and lung metastatic burden (30 fold). Studies using immune compromised mice suggested rapamycin's effect on metastasis is independent of the adaptive immune response. These data suggest a role of mTOR activation in HPV+ HNSCC recurrent/metastatic disease and that adjuvant mTOR inhibition may enhance treatment of resistant, metastatic cell populations at the primary site and limit distant metastasis.
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